Substituted 6,5-fused bicyclic heteroaryl compounds

ABSTRACT

The present invention relates to azole bicyclic heteroaryl compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.provisional application No. 61/798,113, filed Mar. 15, 2013, the entirecontent of which is incorporated herein by reference in its entirety.

INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

The contents of the text file named “EPIZ-019/001US_ST25.txt”, which wascreated on Jun. 1, 2014 and is 1.2 KB in size, are hereby incorporatedby reference in their entireties.

BACKGROUND OF THE INVENTION

There is an ongoing need for new agents as inhibitors of EZH2 mutants,which can be used for treating an EZH2-mediated disorder (e.g., cancer).

SUMMARY OF THE INVENTION

In one aspect, the present invention features an azole bicyclicheteroaryl compound of Formula (I) below or a pharmaceuticallyacceptable salt thereof.

wherein

X₁ is NR₇ or CR₇;

X₂ is N, NR₈, CR₈, O, or S;

X₃ is NR₈, CR₈, O, or S;

X₄ is C or N;

Y₁ is N or CH;

Y₂ is N or CR₆;

Y₃ is N or CR₁₁;

each of R₅, R₉, and R₁₀, independently, is H or C₁-C₆ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl;

each R₆ independently is H, halo, OR_(a), —NR_(a)R_(b), —C(O)R_(a),—C(O)OR_(a), —C(O)NR_(a)R_(b), —NR_(b)C(O)R_(a), —S(O)₂R_(a),—S(O)₂NR_(a)R_(b), or R_(S2), in which each of R_(a) and R_(b),independently is H or R_(S3) and each of R_(S2) and R_(S3) independentlyis C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;or, when applicable, R_(a) and R_(b), together with the N atom to whichthey are attached, form a 4 to 7-membered heterocycloalkyl ring having 0or 1 additional heteroatoms to the N atom; and each of R_(S2), R_(S3),and the 4 to 7-membered heterocycloalkyl ring containing R_(a) andR_(b), is optionally substituted with one or more -Q₂-T₂, wherein Q₂ isa bond or C₁-C₃ alkyl linker each optionally substituted with halo,cyano, hydroxyl or C₁-C₆ alkoxy, and T₂ is H, halo, cyano, —OR_(c),—NR_(c)R_(d), —(NR_(c)R_(d)R_(d′))⁺A⁻, —C(O)R_(c), —C(O)OR_(c),—C(O)NR_(c)R_(d), —NR_(d)C(O)R_(c), —NR_(d)C(O)OR_(c), —S(O)₂R_(c),—S(O)₂NR_(c)R_(d), or R_(S4), in which each of R_(c), R_(d), and R_(d′),independently is H or R_(S5), A⁻ is a pharmaceutically acceptable anion,each of R_(S4) and R_(S5), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl, or R_(c) and R_(d), together with the N atom towhich they are attached, form a 4 to 7-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatoms to the N atom, and each of R_(S4),R_(S5), and the 4 to 7-membered heterocycloalkyl ring containing R_(c)and R_(d), is optionally substituted with one or more -Q₃-T₃, wherein Q₃is a bond or C₁-C₃ alkyl linker each optionally substituted with halo,cyano, hydroxyl or C₁-C₆ alkoxy, and T₃ is selected from the groupconsisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 7-membered heterocycloalkyl, 5 to 6-membered heteroaryl,OR_(e), COOR_(e), —S(O)₂R_(e), —NR_(e)R_(f), and —C(O)NR_(e)R_(f), eachof R_(e) and R_(f) independently being H or C₁-C₆ alkyl optionallysubstituted with OH, O—C₁-C₆ alkyl, or NH—C₁-C₆ alkyl; or -Q₃-T₃ is oxo;or -Q₂-T₂ is oxo; or any two neighboring -Q₂-T₂, together with the atomsto which they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, and 5 to6-membered heteroaryl; provided that -Q₂-T₂ is not H;

each R₇ independently is -Q₄-T₄, in which Q₄ is a bond, C₁-C₄ alkyllinker, or C₂-C₄ alkenyl linker, each linker optionally substituted withhalo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₄ is H, halo, cyano,NR_(g)R_(h), —OR_(g), —C(O)R_(g), —C(O)OR_(g), —C(O)NR_(g)R_(h),—C(O)NR_(g)OR_(h), —NR_(g)C(O)R_(h), —S(O)₂R_(g), or R_(S6), in whicheach of R_(g) and R_(h), independently is H or R_(S7), each of R_(S6)and R_(S7), independently is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl,4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, andeach of R_(S6) and R_(S7) is optionally substituted with one or more-Q₅-T₅, wherein Q₅ is a bond, C(O), C(O)NR_(k), NR_(k)C(O), NR_(k),S(O)₂, NR_(k)S(O)₂, or C₁-C₃ alkyl linker, R_(k) being H or C₁-C₆ alkyl,and T₅ is H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl,cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl and T₅ is optionally substituted with one or moresubstituents selected from the group consisting of halo, C₁-C₆ alkyl,hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-memberedheterocycloalkyl, and 5 to 6-membered heteroaryl except when T₅ is H,halo, hydroxyl, or cyano; or -Q₅-T₅ is oxo; provided that -Q₄-T₄ is notH; and

each of R₈ and R₁₁, independently, is H, halo, hydroxyl, COOH, cyano,R_(S8), OR_(S8), or COOR_(S8), in which R_(S8) is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, amino, mono-C₁-C₆ alkylamino, or di-C₁-C₆alkylamino, and R_(S8) is optionally substituted with one or moresubstituents selected from the group consisting of halo, hydroxyl, COOH,C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino,and di-C₁-C₆ alkylamino;

X is a monocyclic or bicyclic 5 to 10-membered saturated, unsaturated,or aromatic ring containing 2-4 heteroatom ring members and optionallysubstituted with one or more -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₇ is H, —OR_(n)—NR_(n)R_(r), —C(O)R_(n), —C(O)OR^(n),—C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in whicheach of R_(n) and R_(r), independently is H or R_(S10), each of R_(S9)and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl,or R_(n) and R_(r), together with the N atom to which they are attached,form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl; and

n is 0, 1, 2, 3, 4, or 5;

provided that at most one of X₂ and X₃ is O or S, at least one of X₁,X₂, X₃, X₄, Y₁, Y₂, and Y₃ is N or NR₇, and X₁, X₂, X₃, X₄, Y₁, Y₂, andY₃ are assigned such that the

moiety in Formula (I) is a bicyclic heteroaryl system.

In one subset of the compounds of Formula (I) features that X is azoleor a bicyclic ring containing an azole moiety. In one embodiment, X isnot 5-methoxy-1H-pyrrolo[3,2-b]pyridin-7(4H)-one,5-methoxy-1H-pyrazolo[4,3-b]pyridin-7(4H)-one,5-methoxy-1H-imidazo[4,5-b]pyridin-7(4H)-one,5-methoxy-2-methyl-1H-imidazo[4,5-b]pyridin-7(4H)-one, or5-methoxy-3-methyl-1H-pyrazolo[4,3-b]pyridin-7(4H)-one.

In one subset of the compounds of Formula (I), at least one of Y₁, Y₃,and X₄ is N and when X₄ is C, Y₁ is N, Y₂ is CR₆, and Y₃ is CR₁₁, thenX₂ is CR₈.

One subset of the compounds of Formula (I) includes those of Formula(Ia):

wherein R₇ is -Q₄-T₄, wherein Q₄ is a bond or methyl linker, T₄ isoptionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl or optionally substituted 4- to 14-membered heterocycloalkyl.In some compounds, R₇ is tetrahydropyranyl, piperidine substituted by 1,2, or 3 C₁₋₄ alkyl groups, or cyclohexyl substituted by N(C₁₋₄ alkyl)₂wherein one or both of the C₁₋₄ alkyl is optionally substituted withC₁₋₆ alkoxyl.

The compounds of Formulae (I) and (Ia) can include one or more of thefollowing features:

X₄ is C.

X₂ is N or CH.

X₃ is CR₈.

Y₃ is CR₁₁.

R₆ is phenyl substituted with one or more -Q₂-T₂.

R₆ is 5 to 6-membered heteroaryl containing 1-3 heteroatoms selectedfrom N, O, and S and optionally substituted with one or more -Q₂-T₂,provided that the heteroaryl is not thiophenyl.

R₆ is pyridinyl, pyrazolyl, pyrimidinyl, or furyl, each of which isoptionally substituted with one or more -Q₂-T₂.

R₆ is phenyl or 5- or 6-membered heteroaryl substituted with O—C₁₋₆alkyl or NH—C₁₋₆ alkyl, each of which is optionally substituted withhydroxyl, O—C₁₋₃ alkyl or NH—C₁₋₃ alkyl, each of the O—C₁₋₃ alkyl andNH—C₁₋₃ alkyl being optionally further substituted with O—C₁₋₃ alkyl orNH—C₁₋₃ alkyl.

R₆ is

R₆ is halo, C₁-C₃ alkyl optionally substituted with one or more -Q₂-T₂,C₂-C₆ alkenyl optionally substituted with one or more -Q₂-T₂, C₄-C₆cycloalkyl optionally substituted with one or more -Q₂-T₂, C(O)H,OR_(a), or —C(O)R_(a), in which R_(a) is C₁-C₆ alkyl optionallysubstituted with one or more -Q₂-T₂ or 4 to 7-membered heterocycloalkyloptionally substituted with one or more -Q₂-T₂.

R₆ is 4 to 7-membered heterocycloalkyl optionally substituted with oneor more -Q₂-T₂, in which -Q₂-T₂ is oxo or Q₂ is a bond and T₂ is—OR_(c), —NR_(c)R_(d), —C(O)R_(c), —C(O)OR_(c), —S(O)₂R_(c), C₁-C₆alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionallysubstituted with one or more -Q₃-T₃ when R_(c) or R_(d) is not H.

R₆ is piperidinyl, 2,2,6,6-tetramethyl-piperidinyl,1,2,3,6-tetrahydropyridinyl,2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl, piperazinyl,morpholinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, orpyrrolidinyl, each of which is optionally substituted with one or more-Q₂-T₂.

Q₃ is a bond or C₁-C₃ alkyl linker and T₃ is selected from the groupconsisting of C₁-C₃ alkyl, halo, OR_(e), —S(O)₂R_(e), —NR_(e)R_(f), and—C(O)NR_(e)R_(f).

R₇ is C₁-C₆ alkyl, C₂-C₄ alkenyl, C₄-C₆ cycloalkyl, 4 to 7-memberedheterocycloalkyl, or C₆-C₁₀ aryl, each optionally substituted with oneor more -Q₅-T₅.

R₇ is cyclopentyl.

R₇ is unsubstituted C₁-C₆ alkyl.

R₇ is isopropyl or sec-butyl.

R₇ is 5 to 6-membered heterocycloalkyl optionally substituted with oneor more -Q₅-T₅.

R₇ is piperidinyl optionally substituted with one -Q₅-T₅.

R₇ is

R₇ is

R₇

R₇ is

R₇ is

R₇ is

T₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, or 4 to 7-membered heterocycloalkyl.

Q₅ is a bond and T₅ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or 4 to 7-memberedheterocycloalkyl.

Q₅ is CO and T₅ is C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, or 4 to7-membered heterocycloalkyl.

Q₅ is C₁-C₃ alkyl linker and T₅ is H or C₆-C₁₀ aryl.

R₁₁ is H.

Each of R₂ and R₄, independently is H or C₁-C₆ alkyl optionallysubstituted with amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, orC₆-C₁₀ aryl.

Each of R₂ and R₄, independently is C₁-C₃ alkyl optionally substitutedwith C₁-C₆ alkoxyl.

Each of R₂ and R₄ is methyl.

R₁ is H.

R₈ is H, methyl, or ethyl.

R₃ is H.

In some compounds of this invention,

is selected from the group consisting of indolyl, isoindolyl,indolizinyl, benzofuryl, isobenzofuryl, benzo[b]thienyl, benzoxazolyl,benzthiazolyl, benzimidazolyl, benzotriazolyl, benzoxadiazolyl,benzothiadiazolyl, purinyl, indazolyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl, pyrrolopyrazinyl, imidazopyrazinyl,pyrazolopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyridazinyl, imidazopyridazinyl, pyrazolopyridazinyl,furopyridinyl, thienopyridinyl, furopyrazinyl, thienopyrazinyl,oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl,isothiazolopyridinyl, oxadiazolopyridinyl, thiadiazolopyridinyl,triazolopyridinyl, oxazolopyrazinyl, isoxazolopyrazinyl,thiazolopyrazinyl, isothiazolopyrazinyl, oxadiazolopyrazinyl,thiadiazolopyrazinyl, triazolopyrazinyl, furopyrimidinyl,thienopyrimidinyl, furopyridazinyl, thienopyridazinyl,oxazolopyrimidinyl, isoxazolopyrimidinyl, thiazolopyrimidinyl,isothiazolopyrimidinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxazolopyridazinyl, isoxazolopyridazinyl,thiazolopyridazinyl, isothiazolopyridazinyl, oxadiazolopyridazinyl,thiadiazolopyridazinyl, triazolopyridazinyl, and imidazotriazinyl.

In some compounds of this invention,

is selected from the group consisting of

is selected from the group consisting of

In some compounds of this invention,

is selected from the group consisting of

In another aspect, the present invention features an azole bicyclicheteroaryl compound of Formula (II) below or a pharmaceuticallyacceptable salt thereof.

wherein,

-   -   Z₁ is N or CR^(7′),    -   Z₂ is N or CR^(2′), provided when Z₁ is N, Z₂ is N,    -   R^(1′) is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,        unsubstituted or substituted (C₃-C₈)cycloalkyl, unsubstituted or        substituted (C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or —(C₂-C₈)alkenyl,        unsubstituted or substituted (C₅-C₈)cycloalkenyl, unsubstituted        or substituted (C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or        —(C₂-C₈)alkenyl, unsubstituted or substituted        (C₆-C₁₀)bicycloalkyl, unsubstituted or substituted        heterocycloalkyl or —(C₂-C₈)alkenyl, unsubstituted or        substituted heterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or        substituted aryl, unsubstituted or substituted aryl-(C₁-C₈)alkyl        or —(C₂-C₈)alkenyl, unsubstituted or substituted heteroaryl,        unsubstituted or substituted heteroaryl-(C₁-C₈)alkyl or        —(C₂-C₈)alkenyl, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),        —CONR^(a′)NR^(a′)R^(b′);

R^(2′) is hydrogen, (C₁-C₈)alkyl, trifluoromethyl, alkoxy, or halo, inwhich said (C₁-C₈)alkyl is optionally substituted with one to two groupsselected from amino and (C₁-C₃)alkylamino;

R^(7′) is hydrogen, (C₁-C₃)alkyl, or alkoxy;

R^(3′) is hydrogen, (C₁-C₈)alkyl, cyano, trifluoromethyl,—NR^(a′)R^(b′), or halo;

R^(6′) is selected from the group consisting of hydrogen, halo,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—CONR^(a′)NR^(a′)R^(b′), —SR^(a′), —SOR^(a′), —SO₂R^(a′),—SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′),—NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)OR^(a′), —OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′);

wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom the group consisting of —O(C₁-C₆)alkyl(R^(c′))₁₋₂,—S(C₁-C₆)alkyl(R^(c′))₁₋₂, —(C₁-C₆)alkyl(R^(c′))₁₋₂,—(C₁-C₈)alkyl-heterocycloalkyl, (C₃-C₈)cycloalkyl-heterocycloalkyl,halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—OR^(a′), —OC(O)R^(a′), OC(O)NR^(a′)R^(b′), heterocycloalkyl, aryl,heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

wherein any aryl or heteroaryl moiety of said aryl, heteroaryl,aryl(C₁-C₄)alkyl, or heteroaryl(C₁-C₄)alkyl is optionally substituted by1, 2 or 3 groups independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′)),—OR^(a′), —OC(O)R^(a′), and —OC(O)NR^(a′)R^(b′);

R^(a′) and R^(b′) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

each R^(c′) is independently (C₁-C₄)alkylamino, —NR^(a′)SO2R^(b′),—SOR^(a′), —SO₂R^(a′), —NR^(a′)C(O)OR^(a′), —NR^(a′)R^(b′), or—CO₂R^(a′);

X is a monocyclic or bicyclic 5 to 10-membered saturated, unsaturated,or aromatic ring containing 2-4 heteroatom ring members and optionallysubstituted with one or more -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₇ is H, —OR_(n), NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n),—C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in whicheach of R_(n) and R_(r), independently is H or R_(S10), each of R_(S9)and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl,or R_(n) and R_(r), together with the N atom to which they are attached,form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl; and

n is 0, 1, 2, 3, 4, or 5;

provided that at most one of X₂ and X₃ is O or S and X₁, X₂, X₃, X₄, Y₁,Y₂, and Y₃ are assigned such that the

moiety in Formula (I) is a bicyclic heteroaryl system.

One subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of D₁, D₂, and D₃, independently, is CR⁹⁰¹or N, provided that at least one of D₁, D₂, and D₃ is N. D₄ is O, S, orNR⁹⁰². Each R⁹⁰¹ and R⁹⁰², independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, D₁ is N, each of D₂ and D₃,independently, is CR⁹⁰¹, and D₄ is NR⁹⁰². In other compounds, each of D₁and D₂, independently, is CR⁹⁰¹, D₃ is N, and D₄ is NR⁹⁰². In still somecompounds, each of D₁ and D₂ is N, D₃ is CR⁹⁰¹, and D₄ is NR⁹⁰². In yetsome compounds, each of D₁ and D₃ is, independently, CR⁹⁰¹, D₂ is N, andD₄ is NR⁹⁰². In further some compounds, D₁ is N, each of D₂ and D₃,independently, is CR⁹⁰¹, and D₄ is O or S.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of E₁, E₂, and E₄, independently, is CR⁹⁰³or N, provided that at least one of E₁, E₂, and E₄ is N. E₃ is O, S, orNR⁹⁰⁴. Each R⁹⁰³ and R⁹⁰⁴, independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, E₁ is N, each of E₂ and E₄,independently, is CR⁹⁰³, and E₃ is NR⁹⁰⁴. In other compounds, each of E₁and E₄, independently, is CR⁹⁰³, E₂ is N, and E₃ is NR⁹⁰⁴. In stillother compounds, each of E₁ and E₂, independently, is CR⁹⁰³, E₃ isNR⁹⁰⁴, and E₄ is N. In yet other compounds, each of E₁ and E₂,independently, is CR⁹⁰³, E₃ is O, and E₄ is N.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, G₁ is O, S, or NR⁹⁰⁷. Each of G₂, G₃, and G₄,independently, is N or CR⁹⁰⁸, provided that at least one of G₂, G₃, andG₄ is N. Each of R⁹⁰⁵, R⁹⁰⁶, R⁹⁰⁷, and R⁹⁰⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, G₁ is NR⁹⁰⁷, G₂ is CR⁹⁰⁸, and each of G₃and G₄ is N. In other compounds, G₁ is NR⁹⁰⁷, each of G₂ and G₄,independently, is CR⁹⁰⁸ and G₃ is N. In still other compounds, G₁ isNR⁹⁰⁷, each of G₂ and G₄ is N, and G₃ is CR⁹⁰⁸. In yet other compounds,G₁ is NR⁹⁰⁷, G₂ is N, and each of G₃ and G₄, independently, is CR⁹⁰⁸.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of J₁, J₂, J₃, and J₄, independently, is Nor CR⁹¹¹, provided that at least one of J₁, J₂, J₃, and J₄ is N. Each ofR⁹⁰⁹, R⁹¹⁰, and R⁹¹¹, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, each of J₁ is N, and each of J₂, J₃, andJ₄, independently, is CR¹⁹.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of K₁, K₂, K₃, and K₄, independently, is Nor CR⁹¹⁴, provided that at least one of K₁, K₂, K₃, and K₄ is N. Each ofR⁹¹², R⁹¹³, and R⁹¹⁴, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, K₁ is N; and each of K₂, K₃, and K₄,independently, is CR⁹¹⁴. In some compounds, each of K₁ and K₄ is N andeach of K₂ and K₃ independently is CR⁹¹⁴.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of U₁, U₃, and U₄, independently, is N orCR⁹¹⁷, provided that at least one of U₁, U₃, and U₄ is N. U₂ is O, S, orNR⁹¹⁸. Each of R⁹¹⁵, R⁹¹⁶, R⁹¹⁷ and R⁹¹⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t) independentlybeing H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ is oxo; or any twoneighboring -Q₇-T₇ together with the atoms to which they are attachedform a 5- or 6-membered ring optionally containing 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents selected from the group consisting of halo, hydroxyl, COOH,C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino,di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, and 5- or 6-membered heteroaryl. In some compounds, U₁is N; U₂ is NR⁹¹⁸; and each of U₃ and U₄, independently, is CR⁹¹⁷.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing

In the above structure, each of V₁ and V₂, independently, is N or CR⁹¹⁹,provided that at least one of V₁ and V₂ is N. V₃ is O, S, or NR⁹²⁰. Eachof V₄, V₅, and V₆ is O, S, or NR⁹²¹, or CR⁹²²R⁹²³. Each of R⁹¹⁹, R⁹²⁰,R⁹²¹, R⁹²², and R⁹²³, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.

Another subset of the compounds of Formula (I), (Ia), or (II) features Xbeing imidazole-2-yl, imidazol-4-yl, triazol-3-yl,3H-imidazo[4,5-c]pyridin-7-yl, 1H-benzo[d]imidazol-4-yl,1H-indazol-7-yl, isoxazol-3-yl, thiazol-2-yl,1H-pyrazolo[4,3-c]pyridine-7-yl, imidazo[1,2-a]pyridine-8-yl,imidazo[1,2-c]pyrimidin-8-yl,1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-7-yl,1,4,6,7-tetrahydropyrano[3,4-]imidazole-7-yl, or4,5,6,7-tetrahydro-1H-benzo[d]imidazole-4-yl.

The present invention also provides pharmaceutical compositionscomprising one or more pharmaceutically acceptable carriers and one ormore compounds selected from those of any of the Formulae describedherein.

Another aspect of this invention is a method of treating or preventingcancer. The method includes administering to a subject in need thereof atherapeutically effective amount of one or more compounds selected fromthose of any of the Formulae described herein.

Unless otherwise stated, any description of a method of treatmentincludes use of the compounds to provide such treatment or prophylaxisas is described herein, as well as use of the compounds to prepare amedicament to treat or prevent such condition. The treatment includestreatment of human or non-human animals including rodents and otherdisease models.

For example, the method comprises the step of administering to a subjecthaving a cancer with aberrant H3-K27 methylation an effective amount ofone or more compounds of Formulae described herein, wherein thecompound(s) inhibits histone methyltransferase activity of EZH2, therebytreating the cancer. Examples of aberrant H3-K27 methylation may includea global increase in and/or altered distribution of H3-K27 di ortri-methylation within the cancer cell chromatin.

For example, the cancer is selected from the group consisting of cancersthat overexpress EZH2 or other PRC2 subunits, contain loss-of-functionmutations in H3-K27 demethylases such as UTX, or overexpress accessoryproteins such as PHF19/PCL3 capable of increasing and or mislocalizingEZH2 activity (see references in Sneeringer et al. Proc Natl Acad SciUSA 107(49):20980-5, 2010).

For example, the method comprises the step of administering to a subjecthaving a cancer overexpressing EZH2 a therapeutically effective amountof one or more compounds of Formulae described herein, wherein thecompound(s) inhibits histone methyltransferase activity of EZH2, therebytreating the cancer.

For example, the method comprises the step of administering to a subjecthaving a cancer with a loss-of-function mutation in the H3-K27demethylase UTX a therapeutically effective amount of one or morecompounds of Formulae described herein, wherein the compound(s) inhibitshistone methyltransferase activity of EZH2, thereby treating the cancer.

For example, the method comprises the step of administering to a subjecthaving a cancer overexpressing an accessory component(s) of the PRC2,such as PHF19/PCL3, a therapeutically effective amount of one or morecompounds of Formulae described herein, wherein the compound(s) inhibitshistone methyltransferase activity of EZH2, thereby treating the cancer.

In still another aspect, this invention relates to a method ofmodulating the activity of the wild-type EZH2, the catalytic subunit ofthe PRC2 complex which catalyzes the mono- through tri-methylation oflysine 27 on histone H3 (H3-K27). For example, the present inventionrelates to a method of inhibiting the activity of EZH2 in a cell. Thismethod can be conducted either in vitro or in vivo.

In yet another aspect, this invention features to a method of inhibitingin a subject conversion of H3-K27 to trimethylated H3-K27. The methodcomprises administering to a subject a therapeutically effective amountof one or more of the compounds of Formulae described herein to inhibithistone methyltransferase activity of EZH2, thereby inhibitingconversion of H3-K27 to trimethylated H3-K27 in the subject.

For example, the method comprises the step of administering to a subjecthaving a cancer expressing a mutant EZH2 (e.g., a Y641, A677, and/orA687 mutant of EZH2) a therapeutically effective amount of one or morecompounds of Formulae described herein, wherein the compound(s) inhibitshistone methyltransferase activity of EZH2, thereby treating the cancer.

For example, the cancer is selected from the group consisting offollicular lymphoma and diffuse large B-cell lymphoma (DLBCL) ofgerminal center B cell-like (GCB) subtype. For example, the cancer islymphoma, leukemia or melanoma. Preferably, the lymphoma isnon-Hodgkin's lymphoma (NHL), follicular lymphoma or diffuse largeB-cell lymphoma. Alternatively, the leukemia is chronic myelogenousleukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia ormixed lineage leukemia.

For example, the precancerous condition is myelodysplastic syndromes(MDS, formerly known as preleukemia).

For example, the cancer is a hematological cancer.

For example, the cancer is selected from the group consisting of brainand central nervous system (CNS) cancer, head and neck cancer, kidneycancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer,lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer.Preferably, a subject in need thereof is one who had, is having or ispredisposed to developing brain and CNS cancer, kidney cancer, ovariancancer, pancreatic cancer, leukemia, lymphoma, myeloma, and/or sarcoma.Exemplary brain and central CNS cancer includes medulloblastoma,oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexuscarcinoma, choroid plexus papilloma, ependymoma, glioblastoma,meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, andpineoblastoma. Exemplary ovarian cancer includes ovarian clear celladenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serousadenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductaladenocarcinoma and pancreatic endocrine tumor. Exemplary sarcomaincludes chondrosarcoma, clear cell sarcoma of soft tissue, ewingsarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma,and not otherwise specified (NOS) sarcoma. Alternatively, cancers to betreated by the compounds of the present invention are non NHL cancers.

For example, the cancer is selected from the group consisting ofmedulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma,ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma,pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignantrhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroidplexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma,meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma,pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor,extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma,chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma,gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and nototherwise specified (NOS) sarcoma. Preferably, the cancer ismedulloblastoma, ovarian clear cell adenocarcinoma, ovarianendomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma,malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroidplexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma,pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma,skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epithelioidsarcoma, renal medullary carcinoma, diffuse large B-cell lymphoma,follicular lymphoma and/or NOS sarcoma. More preferably, the cancer ismalignant rhabdoid tumor, medulloblastoma and/or atypicalteratoid/rhabdoid tumor.

For example, the method comprises the step of administering to a subjecthaving a cancer expressing a mutant EZH2 (e.g., a Y641, A677, and/orA687 mutant of EZH2) a therapeutically effective amount of one or morecompounds of Formulae described herein, wherein the compound(s) inhibitsactivity (e.g., histone methyltransferase activity) of the mutant EZH2,the wild-type EZH2, or both, thereby treating the cancer.

For example, the method further comprises the steps of performing anassay to detect a mutant EZH2 in a sample comprising cancer cells from asubject in need thereof

In another aspect, the invention features a method of selecting atherapy for a patient having a disease associated with EZH2-mediatedprotein methylation. The method includes the steps of determining thepresence of gene mutation in the EZH2 gene of the subject; andselecting, based on the presence of a gene mutation in the EZH2 gene atherapy for treating the disease. In one embodiment, the therapyincludes the administration of one or more of the compounds of theinvention. In one embodiment, the method further includes administratingone or more of the compounds of the invention to the subject. In oneembodiment, the disease is cancer and the mutation is a Y641, A677,and/or A687 mutation.

In yet another aspect, a method of treatment is provided for a patientin need thereof, the method comprising the steps of determining thepresence of gene mutation in the EZH2 gene and treating the patient inneed thereof, based on the presence of a gene mutation in the EZH2 gene,with a therapy that includes the administration of the compounds of theinvention. In one embodiment, the patient is a cancer patient and themutation is a Y641, A677, and/or A687 mutation.

In still another aspect, this invention relates to a method ofmodulating the activity of the wild-type and mutant histonemethyltransferase EZH2, the catalytic subunit of the PRC2 complex whichcatalyzes the mono- through tri-methylation of lysine 27 on histone H3(H3-K27). For example, the present invention relates to a method ofinhibiting the activity of certain mutant forms of EZH2 in a cell. Themutant forms of EZH2 include a substitution of another amino acidresidue for tyrosine 641 (Y641, also Tyr641) of wild-type EZH2. Themethod includes contacting the cell with an effective amount of one ormore of the compounds of any Formula described herein. This method canbe conducted either in vitro or in vivo.

In yet another aspect, this invention features to a method of inhibitingin a subject conversion of H3-K27 to trimethylated H3-K27. The methodcomprises administering to a subject expressing a mutant EZH2 (e.g., aY641, A677, and/or A687 mutant of EZH2) a therapeutically effectiveamount of one or more of the compounds of any Formula described hereinto inhibit histone methyltransferase activity of EZH2, therebyinhibiting conversion of H3-K27 to trimethylated H3-K27 in the subject.For example, the histone methyltransferase activity inhibited is that ofthe Y641 mutant of EZH2. For example, the compound of this inventionselectively inhibits histone methyltransferase activity of the Y641mutant of EZH2. For example, the Y641 mutant of EZH2 is selected fromthe group consisting of Y641C, Y641F, Y641H, Y641N, and Y641S.

The method of inhibiting in a subject conversion of H3-K27 totrimethylated H3-K27 may also comprise performing an assay to detect amutant EZH2 (e.g., a Y641, A677, and/or A687 mutant of EZH2) in a samplefrom a subject before administering to the subject expressing a mutantEZH2 a therapeutically effective amount of one or more of the compoundsof any Formula described herein. For example, performing the assay todetect the mutant EZH2 includes whole-genome resequencing or targetregion resequencing that detects a nucleic acid encoding the mutantEZH2. For example, performing the assay to detect the mutant EZH2includes contacting the sample with an antibody that binds specificallyto a polypeptide or fragment thereof characteristic of the mutant EZH2.For example, performing the assay to detect the mutant EZH2 includescontacting the sample under highly stringent conditions with a nucleicacid probe that hybridizes to a nucleic acid encoding a polypeptide orfragment thereof characteristic of the mutant EZH2.

Further, the invention also relates to a method of identifying aninhibitor of a mutant EZH2, the wild-type EZH2, or both. The methodcomprises the steps of combining an isolated EZH2 with a histonesubstrate, a methyl group donor, and a test compound, wherein thehistone substrate comprises a form of H3-K27 selected from the groupconsisting of unmethylated H3-K27, monomethylated H3-K27, dimethylatedH3-K27, and any combination thereof; and performing an assay to detectmethylation of H3-K27 (e.g., formation of trimethylated H3-K27) in thehistone substrate, thereby identifying the test compound as an inhibitorof the EZH2 when methylation of H3-K27 (e.g., formation of trimethylatedH3-K27) in the presence of the test compound is less than methylation ofH3-K27 (e.g., formation of trimethylated H3-K27) in the absence of thetest compound.

In one embodiment, performing the assay to detect methylation of H3-K27in the histone substrate comprises measuring incorporation of labeledmethyl groups.

In one embodiment, the labeled methyl groups are isotopically labeledmethyl groups.

In one embodiment, performing the assay to detect methylation of H3-K27in the histone substrate comprises contacting the histone substrate withan antibody that binds specifically to trimethylated H3-K27.

Also within the scope of the invention is a method of identifying aselective inhibitor of a mutant EZH2. The method comprises the steps ofcombining an isolated mutant EZH2 with a histone substrate, a methylgroup donor, and a test compound, wherein the histone substratecomprises a form of H3-K27 selected from the group consisting ofmonomethylated H3-K27, dimethylated H3-K27, and a combination ofmonomethylated H3-K27 and dimethylated H3-K27, thereby forming a testmixture; combining an isolated wild-type EZH2 with a histone substrate,a methyl group donor, and a test compound, wherein the histone substratecomprises a form of H3-K27 selected from the group consisting ofmonomethylated H3-K27, dimethylated H3-K27, and a combination ofmonomethylated H3-K27 and dimethylated H3-K27, thereby forming a controlmixture; performing an assay to detect trimethylation of the histonesubstrate in each of the test mixture and the control mixture;calculating the ratio of (a) trimethylation with the mutant EZH2 and thetest compound (M+) to (b) trimethylation with the mutant EZH2 withoutthe test compound (M−); calculating the ratio of (c) trimethylation withwild-type EZH2 and the test compound (WT+) to (d) trimethylation withwild-type EZH2 without the test compound (WT−); comparing the ratio(a)/(b) with the ratio (c)/(d); and identifying the test compound as aselective inhibitor of the mutant EZH2 when the ratio (a)/(b) is lessthan the ratio (c)/(d).

The present invention further provides a method of identifying a subjectas a candidate for treatment with one or more compounds of theinvention. The method comprises the steps of performing an assay todetect a mutant EZH2 in a sample from a subject; and identifying asubject expressing a mutant EZH2 as a candidate for treatment with oneor more compounds of the invention, wherein the compound(s) inhibitshistone methyltransferase activity of EZH2.

Still another aspect of the invention is a method of inhibitingconversion of H3-K27 to trimethylated H3-K27. The method comprises thestep of contacting a mutant EZH2, the wild-type EZH2, or both, with ahistone substrate comprising H3-K27 and an effective amount of acompound of the present invention, wherein the compound inhibits histonemethyltransferase activity of EZH2, thereby inhibiting conversion ofH3-K27 to trimethylated H3-K27.

Further, the compounds or methods described herein can be used forresearch (e.g., studying epigenetic enzymes) and other non-therapeuticpurposes.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting. In the case ofconflict between the chemical structures and names of the compoundsdisclosed herein, the chemical structures will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel azole bicyclic heteroarylcompounds, synthetic methods for making the compounds, pharmaceuticalcompositions containing them and various uses of the compounds.

The present invention provides the compounds of Formula (I):

In this formula:

X₁ is NR₇ or CR₇;

X₂ is N, NR₈, CR₈, O, or S;

X₃ is NR₈, CR₈, O, or S;

X₄ is C or N;

Y₁ is N or CH;

Y₂ is N or CR₆;

Y₃ is N, or CR₁₁;

each of R₅, R₉, and R₁₀, independently, is H or C₁-C₆ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl;

each R₆ independently is H, halo, OR_(a), —NR_(a)R_(b), —C(O)R_(a),—C(O)OR_(a), —C(O)NR_(a)R_(b), —NR_(b)C(O)R_(a), —S(O)₂R_(a),—S(O)₂NR_(a)R_(b), or R_(S2), in which each of R_(a) and R_(b),independently is H or R_(S3) and each of R_(S2) and R_(S3),independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl; or R_(a) and R_(b), together with the N atom towhich they are attached, form a 4 to 7-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatoms to the N atom; and each of R_(S2),R_(S3), and the 4 to 7-membered heterocycloalkyl ring containing R_(a)and R_(b), is optionally substituted with one or more -Q₂-T₂, wherein Q₂is a bond or C₁-C₃ alkyl linker each optionally substituted with halo,cyano, hydroxyl or C₁-C₆ alkoxy, and T₂ is H, halo, cyano, —OR_(c),—NR_(c)R_(d), —(NR_(c)R_(d)R_(d′))⁺A⁻, —C(O)R_(c), —C(O)OR_(c),—C(O)NR_(c)R_(d), —NR_(d)C(O)R_(c), —NR_(d)C(O)OR_(c), —S(O)₂R_(c),—S(O)₂NR_(c)R_(d), or R_(S4), in which each of R_(c), R_(d), and R_(d′),independently is H or R_(S5), A⁻ is a pharmaceutically acceptable anion,each of R_(S4) and R_(S5), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl, or R_(c) and R_(d), together with the N atom towhich they are attached, form a 4 to 7-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatoms to the N atom, and each of R_(S4),R_(S5), and the 4 to 7-membered heterocycloalkyl ring containing R_(c)and R_(d), is optionally substituted with one or more -Q₃-T₃, wherein Q₃is a bond or C₁-C₃ alkyl linker each optionally substituted with halo,cyano, hydroxyl or C₁-C₆ alkoxy, and T₃ is selected from the groupconsisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 7-membered heterocycloalkyl, 5 to 6-membered heteroaryl,OR_(e), COOR_(e), —S(O)₂R_(e), —NR_(e)R_(f), and —C(O)NR_(e)R_(f), eachof R_(e) and R_(f) independently being H or C₁-C₆ alkyl optionallysubstituted with OH, O—C₁-C₆ alkyl, or NH—C₁-C₆ alkyl; or -Q₃-T₃ is oxo;or -Q₂-T₂ is oxo; or any two neighboring -Q₂-T₂, together with the atomsto which they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, and 5 to6-membered heteroaryl; provided that -Q₂-T₂ is not H;

each R₇ independently is -Q₄-T₄, in which Q₄ is a bond, C₁-C₄ alkyllinker, or C₂-C₄ alkenyl linker, each linker optionally substituted withhalo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₄ is H, halo, cyano,NR_(g)R_(h), —OR_(g), —C(O)R_(g), —C(O)OR_(g), —C(O)NR_(g)R_(h),—C(O)NR_(g)OR_(h), —NR_(g)C(O)R_(h), —S(O)₂R_(g), or R_(S6), in whicheach of R_(g) and R_(h), independently is H or R_(S7), each of R_(S6)and R_(S7), independently is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl,4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, andeach of R_(S6) and R_(S7) is optionally substituted with one or more-Q₅-T₅, wherein Q₅ is a bond, C(O), C(O)NR_(k), NR_(k)C(O), NR_(k),S(O)₂, NR_(k)S(O)₂, or C₁-C₃ alkyl linker, R_(k) being H or C₁-C₆ alkyl,and T₅ is H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl,cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl and T₅ is optionally substituted with one or moresubstituents selected from the group consisting of halo, C₁-C₆ alkyl,hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-memberedheterocycloalkyl, and 5 to 6-membered heteroaryl except when T₅ is H,halo, hydroxyl, or cyano; or -Q₅-T₅ is oxo; provided that -Q₄-T₄ is notH; and

each of R₈ and R₁₁, independently, is H, halo, hydroxyl, COOH, cyano,R_(S8), OR_(S8), or COOR_(S8), in which R_(S8) is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, amino, mono-C₁-C₆ alkylamino, or di-C₁-C₆alkylamino, and R_(S8) is optionally substituted with one or moresubstituents selected from the group consisting of halo, hydroxyl, COOH,C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino,and di-C₁-C₆ alkylamino;

X is a monocyclic or bicyclic 5 to 10-membered saturated, unsaturated,or aromatic ring containing 2-4 heteroatom ring members and optionallysubstituted with one or more -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n),—C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in whicheach of R_(n) and R_(r), independently is H or R_(S10), each of R_(S9)and R_(S10)), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl,or R_(n) and R_(r), together with the N atom to which they are attached,form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl; and

n is 0, 1, 2, 3, 4, or 5;

provided that at most one of X₂ and X₃ is O or S, at least one of X₁,X₂, X₃, X₄, Y₁, Y₂, and Y₃ is N or NR₇ as applicable, and X₁, X₂, X₃,X₄, Y₁, Y₂, and Y₃ are assigned such that the

moiety in Formula (I) is a bicyclic heteroaryl system.

The compounds of Formula (I) can have one or more of the followingfeatures:

For example, at least one of Y₁, Y₃, and X₄ is N and when X₄ is C, Y₁ isN, Y₂ is CR₆, and Y₃ is CR₁₁, then X₂ is CR₈.

For example,

For example, X₄ is C.

For example, X₂ is N or CH.

For example, X₃ is CR₈.

For example, Y₃ is CR₁₁.

For example, R₆ is phenyl substituted with one or more -Q₂-T₂.

For example, R₆ is 5 to 6-membered heteroaryl containing 1-3 heteroatomsselected from N, O, and S and optionally substituted with one or more-Q₂-T₂, provided that the heteroaryl is not thiophenyl.

For example, R₆ is pyridinyl, pyrazolyl, pyrimidinyl, or furyl, each ofwhich is optionally substituted with one or more -Q₂-T₂.

For example, R₆ is phenyl or 5- or 6-membered heteroaryl substitutedwith O—C₁₋₆ alkyl or NH—C₁₋₆ alkyl, each of which is optionallysubstituted with hydroxyl, O—C₁₋₃ alkyl or NH—C₁₋₃ alkyl, each of theO—C₁₋₃ alkyl and NH—C₁₋₃ alkyl being optionally further substituted withO—C₁₋₃ alkyl or NH—C₁₋₃ alkyl.

For example, R₆ is

For example, R₆ is ethynyl.

For example, R₆ is ethynyl substituted with one or more -Q₂-T₂, in whichQ₂ is a bond or C₁-C₃ alkyl linker and T₂ is C₁-C₆ alkyl, C₃-C₆cycloalkyl, or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl,piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl,tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, andmorpholinyl, and the like) optionally substituted with one or more-Q₃-T₃.

For example, R₆ is

For example, R₆ is halo (e.g., fluorine, chlorine, bromine, and iodine).

For example, R₆ is C₁-C₃ alkyl substituted with one or more -Q₂-T₂.

For example, R₆ is C₂-C₆ alkenyl or C₄-C₆ cycloalkyl each optionallysubstituted with one or more -Q₂-T₂.

For example, R₆ is C(O)H.

For example, R₆ is OR, or —C(O)R_(a).

For example, R_(a) is C₁-C₆ alkyl or 4 to 7-membered heterocycloalkyl(e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, and morpholinyl, and thelike), which is optionally substituted with one or more -Q₂-T₂.

For example, R₆ is —NR_(a)R_(b), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), —NR_(b)C(O)R_(a), —S(O)₂R_(a), or —S(O)₂NR_(a)R_(b).

For example, each of R_(a) and R_(b), independently is H or C₁-C₆ alkyloptionally substituted with one or more -Q₂-T₂.

For example, one of R_(a) and R_(b) is H.

For example, R_(a) and R_(b), together with the N atom to which they areattached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl,1,2,3,6-tetrahydropyridinyl, piperazinyl, and morpholinyl, and the like)and the ring is optionally substituted with one or more -Q₂-T₂.

For example, R₆ is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl,piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, and morpholinyl, and thelike) optionally substituted with one or more -Q₂-T₂.

For example, R₆ is piperidinyl, 2,2,6,6-tetramethyl-piperidinyl,1,2,3,6-tetrahydropyridinyl,2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl, piperazinyl,morpholinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, orpyrrolidinyl, each of which is optionally substituted with one or more-Q₂-T₂.

For example, R₆ is 4 to 7-membered heterocycloalkyl optionallysubstituted with one or more -Q₂-T₂, and -Q₂-T₂ is oxo or Q₂ is a bondand T₂ is —OR_(c), —NR_(c)R_(d), —C(O)R_(c), —C(O)OR_(c), —S(O)₂R_(c),C₁-C₆ alkyl, or 4 to 7-membered heterocycloalkyl, each of which isoptionally substituted with one or more -Q₃-T₃ when R_(c) or R_(d) isnot H.

For example, -Q₂-T₂ is oxo.

For example, Q₂ is a bond.

For example, Q₂ is an unsubstituted C₁-C₃ alkyl linker.

For example, T₂ is C₁-C₆ alkyl or C₆-C₁₀ aryl, each optionallysubstituted with one or more -Q₃-T₃.

For example, T₂ is an unsubstituted substituted straight chain C₁-C₆ orbranched C₃-C₆ alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl.

For example, T₂ is phenyl.

For example, T₂ is halo (e.g., fluorine, chlorine, bromine, and iodine).

For example, T₂ is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl,piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, and morpholinyl, and thelike) optionally substituted with one or more -Q₃-T₃.

For example, T₂ is —OR_(c), —NR_(c)R_(d), —C(O)R_(c), —C(O)OR_(c), or—S(O)₂R_(c).

For example, T₂ is —(NR_(c)R_(d)R_(d′))⁺A⁻, —C(O)NR_(c)R_(d),—NR_(d)C(O)R_(c), —NR_(d)C(O)OR_(c), or —S(O)₂NR_(c)R_(d).

For example, Q₂ is a bond or methyl linker and T₂ is H, halo, —OR_(c),—NR_(c)R_(d), —(NR_(c)R_(d)R_(d′))⁺A⁻, or —S(O)₂NR_(c)R_(d).

For example, R_(c) is C₁-C₆ alkyl or 4 to 7-membered heterocycloalkyl(e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, and morpholinyl, and thelike), which is optionally substituted with one or more -Q₃-T₃.

For example, each of R_(c) and R_(d), independently is H or C₁-C₆ alkyloptionally substituted with one or more -Q₃-T₃

For example, R_(c) is H.

For example, R_(d) is H.

For example, R_(c) and R_(d), together with the N atom to which they areattached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl,1,2,3,6-tetrahydropyridinyl, piperazinyl, and morpholinyl, and the like)and the ring is optionally substituted with one or more -Q₃-T₃.

For example, Q₂ is a bond and T₂ is —OR_(c), —NR_(c)R_(d), —C(O)R_(c),—C(O)OR_(c), —S(O)₂R_(c), C₁-C₆ alkyl, or 4 to 7-memberedheterocycloalkyl, each of which is optionally substituted with one ormore -Q₃-T₃ when R_(c) or R_(d) is not H.

For example, -Q₃-T₃ is oxo.

For example, T₂ is 4 to 7-membered heterocycloalkyl or C₃-C₈ cycloalkyland one or more -Q₃-T₃ are oxo.

For example, Q₃ is a bond or unsubstituted or substituted C₁-C₃ alkyllinker.

For example, T₃ is H, halo, 4 to 7-membered heterocycloalkyl, C₁-C₃alkyl, OR_(e), COOR_(e), —S(O)₂R_(e), —NR_(e)R_(f), or —C(O)NR_(e)R_(f).

For example, one of R_(d) and R_(e) is H.

For example, Q₃ is a bond or C₁-C₃ alkyl linker and T₃ is selected fromthe group consisting of C₁-C₃ alkyl, halo, OR_(e), —S(O)₂R_(e),—NR_(e)R_(f), and —C(O)NR_(e)R_(f).

For example, R_(e) is H.

For example, R_(f) is H.

For example, R₇ is C₁-C₆ alkyl optionally substituted with one or more-Q₅-T₅.

For example, R₇ is C₃-C₈ cycloalkyl optionally substituted with one ormore -Q₅-T₅.

For example, R₇ is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl,piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, and morpholinyl, and thelike) optionally substituted with one or more -Q₅-T₅.

For example, R₇ is cyclopentyl.

For example, R₇ is isopropyl or sec-butyl.

For example, R₇ is 5 to 6-membered heterocycloalkyl optionallysubstituted with one or more -Q₅-T₅.

For example, R₇ is piperidinyl optionally substituted with one -Q₅-T₅.

For example, R₇ is tetrahydropyran or

For example, R₇ is

For example, R₇ is

For example, R₇ is

For example, R₇ is

For example, R₇ is

For example, R₇ is Q₄-T₄, Q₄ is a bond and T₄ is 4 to 7-memberedheterocycloalkyl or C₃-C₈ cycloalkyl substituted with one or more-Q₅-T₅.

For example, -Q₅-T₅ is oxo.

For example, T₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, or 4 to 7-membered heterocycloalkyl.

For example, Q₅ is a bond and T₅ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or 4to 7-membered heterocycloalkyl.

For example, Q₅ is CO and T₅ is C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₈cycloalkyl, or 4 to 7-membered heterocycloalkyl.

For example, T₅ is C₁-C₆ alkyl optionally substituted with halo,hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, or C₃-C₈ cycloalkyl.

For example, Q₅ is C₁-C₃ alkyl linker and T₅ is H or C₆-C₁₀ aryl.

For example, X is azole or a bicyclic ring containing an azole moiety.

For example, X is not 5-methoxy-1H-pyrrolo[3,2-b]pyridin-7(4H)-one,5-methoxy-1H-pyrazolo[4,3-b]pyridin-7(4H)-one,5-methoxy-1H-imidazo[4,5-b]pyridin-7(4H)-one,5-methoxy-2-methyl-1H-imidazo[4,5-b]pyridin-7(4H)-one, or5-methoxy-3-methyl-1H-pyrazolo[4,3-b]pyridin-7(4H)-one.

For example, X is imidazol-2-yl, imidazol-4-yl, triazol-3-yl,3H-imidazo[4,5-c]pyridin-7-yl, 1H-benzo[d]imidazol-4-yl,1H-indazol-7-yl, isoxazol-3-yl, thiazol-2-yl,1H-pyrazolo[4,3-c]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-c]pyrimidin-8-yl,1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-7-yl,1,4,6,7-tetrahydropyrano[3,4-]imidazol-7-yl, or4,5,6,7-tetrahydro-1H-benzo[d]imidazol-4-yl.

For example,

is selected from indolyl, isoindolyl, indolizinyl, benzofuryl,isobenzofuryl, benzo[b]thienyl, benzoxazolyl, benzthiazolyl,benzimidazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl,purinyl, indazolyl, pyrrolopyridinyl, imidazopyridinyl,pyrazolopyridinyl, pyrrolopyrazinyl, imidazopyrazinyl,pyrazolopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyridazinyl, imidazopyridazinyl, pyrazolopyridazinyl,furopyridinyl, thienopyridinyl, furopyrazinyl, thienopyrazinyl,oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl,isothiazolopyridinyl, oxadiazolopyridinyl, thiadiazolopyridinyl,triazolopyridinyl, oxazolopyrazinyl, isoxazolopyrazinyl,thiazolopyrazinyl, isothiazolopyrazinyl, oxadiazolopyrazinyl,thiadiazolopyrazinyl, triazolopyrazinyl, furopyrimidinyl,thienopyrimidinyl, furopyridazinyl, thienopyridazinyl,oxazolopyrimidinyl, isoxazolopyrimidinyl, thiazolopyrimidinyl,isothiazolopyrimidinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxazolopyridazinyl, isoxazolopyridazinyl,thiazolopyridazinyl, isothiazolopyridazinyl, oxadiazolopyridazinyl,thiadiazolopyridazinyl, triazolopyridazinyl, and imidazotriazinyl.

For example,

is selected from

For example,

is selected from

For example,

is selected from

For example, X is

In the above structure, each of D₁, D₂, and D₃, independently, is CR⁹⁰¹or N, provided that at least one of D₁, D₂, and D₃ is N. D₄ is O, S, orNR⁹⁰². Each R⁹⁰¹ and R⁹⁰², independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, each of D₂ and D₃, independently, isCR⁹⁰¹ and D₄ is NR⁹⁰². In other compounds, each of D₁ and D₂,independently, is CR⁹⁰¹, D₃ is N, and D₄ is NR⁹⁰². In other compounds,each of D₁ and D₂ is N, D₃ is CR⁹⁰¹, and D₄ is NR⁹⁰². In still othercompounds, each of D₁ and D₃ is, independently, CR⁹⁰¹, D₂ is N, and D₄is NR⁹⁰². In further other compounds, D₁ is N, each of D₂ and D₃,independently, is CR⁹⁰¹, and D₄ is O or S.

For example, X is

In the above structure, each of E₁, E₂, and E₄, independently, is CR⁹⁰³or N, provided that at least one of E₁, E₂, and E₄ is N. E₃ is O, S, orNR⁹⁰⁴. Each R⁹⁰³ and R⁹⁰⁴, independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q-T₈ is oxo; or -Q₇-T₇ is oxo;or any two neighboring -Q₇-T₇ together with the atoms to which they areattached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, E₁ is N, each of E₂ and E₄,independently, is CR⁹⁰³, and E₃ is NR⁹⁰⁴. In other compounds, each of E₁and E₄, independently, is CR⁹⁰³, E₂ is N, and E₃ is NR⁹⁰⁴. In stillother compounds, each of E₁ and E₂, independently, is CR⁹⁰³, E₃ isNR⁹⁰⁴, and E₄ is N. In further other compounds, each of E₁ and E₂,independently, is CR⁹⁰³, E₃ is O, and E₄ is N.

For example, X is

In the above structure, G₁ is O, S, or NR⁹⁰⁷. Each of G₂, G₃, and G₄,independently, is N or CR⁹⁰⁸, provided that at least one of G₂, G₃, andG₄ is N. Each of R⁹⁰⁵, R⁹⁰⁶, R⁹⁰⁷, and R⁹⁰⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, G₁ is NR⁹⁰⁷, G₂ is CR⁹⁰⁸, and each of G₃and G₄ is N. In other compounds, G₁ is NR⁹⁰⁷, each of G₂ and G₄,independently, is CR⁹⁰⁸, and G₃ is N. In still other compounds, G₁ isNR⁹⁰⁷, each of G₂ and G₄ is N, and G₃ is CR⁹⁰⁸. In further othercompounds, G₁ is NR⁹⁰⁷, G₂ is N, and each of G₃ and G₄, independently,is CR⁹⁰⁸.

For example, X is

In the above structure, each of J₁, J₂, J₃, and J₄, independently, is Nor CR⁹¹¹, provided that at least one of J₁, J₂, J₃, and J₄ is N. Each ofR⁹⁰⁹, R⁹¹⁰, and R⁹¹¹, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r) together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, each of J₁ is N, and each of J₂, J₃, andJ₄, independently, is CR⁹¹¹.

For example, X is

In the above structure, each of K₁, K₂, K₃, and K₄, independently, is Nor CR⁹¹⁴, provided that at least one of K₁, K₂, K₃, and K₄ is N. Each ofR⁹¹², R⁹¹³, and R⁹¹⁴, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, K₁ is N and each of K₂, K₃, and K₄,independently, is CR⁹¹⁴. In other compounds, each of K₁ and K₄ is N andeach of K₂ and K₃ independently, is CR⁹¹⁴.

For example, X is

In the above structure, each of U₁, U₃, and U₄, independently, is N orCR⁹¹⁷, provided at least one of U₁, U₃, and U₄ is N. U₂ is O, S, orNR⁹¹⁸. Each of R⁹¹⁵, R⁹¹⁶, R⁹¹⁷, and R⁹¹⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, U₁ is N, U₂ is NR⁹¹⁸, and each of U₃ andU₄, independently, is CR⁹¹⁷.

For example, X is

In the above structure, each of V₁ and V₂, independently, is N or CR⁹¹⁹,provided that at least one of V₁ and V₂ is N. V₃ is O, S, or NR⁹²⁰. Eachof V₄, V₅, and V₆ is O, S, or NR⁹²¹, or CR⁹²²R⁹²³; and each of R⁹¹⁹,R⁹²⁰, R⁹²¹, R⁹²², and R⁹²³, independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s), andR_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇is oxo; or any two neighboring -Q₇-T₇ together with the atoms to whichthey are attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.

One subset of the compounds of Formula (I) includes those of Formula(Ia):

wherein R₇ is Q₄-T₄, wherein Q₄ is a bond or methyl linker, T₄ isoptionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl or optionally substituted 4- to 14-membered heterocycloalkyl;and R₆, each of X₂, X₃, X₄, Y₁, Y₃, X, and n is as defined herein forFormula (I). In some compounds, R₇ is tetrahydropyranyl, piperidinesubstituted by 1, 2, or 3 C₁₋₄ alkyl groups, or cyclohexyl substitutedby N(C₁₋₄ alkyl)₂ wherein one or both of the C₁₋₄ alkyl is optionallysubstituted with C₁₋₆ alkoxyl.

In addition to the above-described features of the compounds of thisinvention, where applicable, the compounds of Formula (Ia) can includeone or more of the following features:

For example, T₄ is alkyl such as i-propyl.

For example, T₄ is

For example, T₄ is

in which R′″ is T₅, —C(O)T₅, or S(O)₂T₅, T₅ being as defined herein forFormula (I).

For example, the compounds of Formula (I) include those of Formula (Ib):

or a pharmaceutically acceptable salt thereof; wherein

n₅ is 0, 1, or 2;

R⁵⁰¹ is C(H) or N;

R⁵⁰⁶ is C₁-C₆ alkyl, piperidine substituted by 1, 2, or 3 C₁₋₄ alkylgroups, or cyclohexyl substituted by N(C₁₋₄ alkyl)₂ wherein one or bothof the C₁₋₄ alkyl is optionally substituted with C₁₋₆ alkoxyl;

R⁵⁰⁷ is morpholine, piperazine, piperidine, diazepane, pyrrolidine,azetidine, O—C₁₋₆ alkyl, NH—C₁₋₆ alkyl, or O-heterocycle, wherein theheterocycle is a 4-7 membered heterocycle containing an oxygen ornitrogen, or both, and wherein the nitrogen can optionally besubstituted with C₁₋₃ alkyl; wherein the piperazine, piperidine,diazepane, pyrrolidine or azetidine groups can be optionally furthersubstituted with OH, C₁₋₆ alkyl, or O—C₁₋₃ alkyl; and wherein each ofthe O—C₁₋₆ alkyl and NH—C₁₋₆ alkyl is optionally substituted withhydroxyl, O—C₁₋₃ alkyl or NH—C₁₋₃ alkyl, each of the O—C₁₋₃ alkyl andNH—C₁₋₃ alkyl being optionally further substituted with O—C₁₋₃ alkyl orNH—C₁₋₃ alkyl; and

each of X₂, X₃, X₄, Y₁, Y₃, X and n is as defined herein for Formula(I).

In addition to the above-described features of the compounds of thisinvention, where applicable, the compounds of Formula (Ib) can includeone or more of the following features.

For example, R⁵⁰¹ is C(H), and R⁵⁰⁷ is piperidine; diazepane;pyrrolidine; azetidine; 0-C₁₋₆ alkyl; or O-heterocycle, wherein theheterocycle is a 4-7 membered heterocycle containing an oxygen ornitrogen, or both, and wherein the nitrogen can optionally besubstituted with C₁₋₃ alkyl; wherein the piperidine, diazepane,pyrrolidine or azetidine groups can be optionally further substitutedwith OH, C₁₋₆ alkyl, or O—C₁₋₃ alkyl.

For example, R⁵⁰¹ is C(H) and R⁵⁰⁷ is piperidine, diazepane,pyrrolidine, azetidine or O—C₁₋₆ alkyl, wherein the piperidine,diazepane, pyrrolidine or azetidine groups can be optionally furthersubstituted with OH or C₁₋₆ alkyl.

For example, R⁵⁰¹ is C(H), R⁵⁰⁷ is piperazine optionally furthersubstituted with C₁₋₆ alkyl, and R⁵⁰⁶ is piperidine substituted by 1, 2,or 3 C₁₋₄ alkyl groups.

For example, R⁵⁰¹ is N, and R⁵⁰⁷ is morpholine, piperidine, piperazine,diazepane, pyrrolidine, azetidine or O—C₁₋₆ alkyl, wherein thepiperidine, piperazine, diazepane, pyrrolidine or azetidine groups canbe optionally further substituted with OH or C₁₋₆ alkyl.

For example, R₁ is H, methyl, or ethyl, and R₂ is halo, cyano, C₁-C₆alkoxyl optionally substituted with C₁-C₆ alkoxyl, C₁-C₃ alkyloptionally substituted with C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino,di-C₁-C₆ alkylamino, optionally substituted 4 to 6-memberedheterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl), optionally substituted phenyl, or optionally substituted5- or 6-membered heteroaryl (e.g., pyridinyl, pyrazolyl, pyrimidinyl,quinolinyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,furyl, or thienyl).

For example, R⁵⁰⁶ is C₁-C₆ alkyl such as i-propyl.

For example, R⁵⁰⁶ is

For example, R⁵⁰⁶ is

For example, R⁵⁰⁶ is

For example, R⁵⁰⁶ is

For example, R⁵⁰⁶ is

For example, R⁵⁰⁶ is

For example, when R⁵⁰¹ is C(H), R⁵⁰⁷ is piperidine or diazepane, whichare substituted with OH or C₁₋₆ alkyl, or when R⁵⁰¹ is N, R⁵⁰⁷ ispiperidine, piperazine, or diazepane, which are optionally furthersubstituted with OH or C₁₋₆ alkyl.

For example, when R⁵⁰¹ is C(H), R⁵⁰⁷ is piperidine substituted with C₁₋₆alkyl, or when R⁵⁰¹ is N, R⁵⁰⁷ is piperidine substituted with OH orpiperazine substituted with C₁₋₆ alkyl.

For example, when R⁵⁰¹ is N, R⁵⁰⁷ is unsubstituted piperazine.

For example, n₅ is 0 or 1.

For example, when R⁵⁰¹ is C(H) or N, R⁵⁰⁷ is O—C₁₋₆ alkyl orO-heterocycle, and n₅ is 1.

For example, when R⁵⁰¹ is C(H), R⁵⁰⁷ is unsubstituted piperazine andR⁵⁰⁶ is piperidine substituted by 1, 2, or 3 C₁₋₄ alkyl groups.

For example, R⁵⁰⁷ is O—C₂₋₃ alkyl substituted with O—C₁₋₂ alkyl, e.g.,—OCH₂CH₂OCH₃.

For example, n is 0, 1, or 2.

For example, the compounds of Formula (I) include those of Formula (Ic):

or a pharmaceutically acceptable salt thereof;wherein

n₆ is 0, 1 or 2;

R⁶⁰⁶ is C₁-C₆ alkyl, tetrahydropyranyl, piperidine substituted by 1, 2,or 3 C₁₋₄ alkyl groups, or cyclohexyl substituted by N(C₁₋₄ alkyl)₂wherein one or both of the C₁₋₄ alkyl is optionally substituted withC₁₋₆ alkoxyl;

R⁶⁰⁷ is morpholine, piperidine, piperazine, pyrrolidine, diazepane,oxetane, azetidine or O—C₁₋₆ alkyl, wherein the piperidine, diazepane,oxetane or azetidine groups can be optionally further substituted withone or more C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, or 4 to6-membered heterocycloalkyl; and

each of X₂, X₃, X₄, Y₁, Y₃, X and n is as defined herein for Formula(I).

In addition to the above-described features of the compounds of thisinvention, where applicable, the compounds of Formula (Ic) can includeone or more of the following features:

For example, R⁶⁰⁶ is C₁-C₆ alkyl such as i-propyl.

For example, R⁶⁰⁶ is

For example, R⁶⁰⁶ is

For example, R⁶⁰⁶ is

For example, R⁶⁰⁶ is

For example, R⁶⁰⁶ is

For example, R⁶⁰⁶ is

For example, R⁶⁰⁷ is piperidine or oxetane, each of which is substitutedwith C₁₋₆ alkyl.

For example, R⁶⁰⁷ is piperidine substituted with CH₂CF₃, cyclopropyl,cyclobutyl, or oxetane.

For example, n₆ is 0 or 1.

For example, n is 0, 1, or 2.

The compounds of formula (Ia), (Ib), and (Ic) may further include thefollowing features:

For example, X is

In the above structure, each of D₁, D₂, and D₃, independently, is CR⁹⁰¹or N, provided that at least one of D₁, D₂, and D₃ is N. D₄ is O, S, orNR⁹⁰². Each R⁹⁰¹ and R⁹⁰², independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, each of D₂ and D₃, independently, isCR⁹⁰¹ and D₄ is NR⁹⁰². In other compounds, each of D₁ and D₂,independently, is CR⁹⁰¹, D₃ is N and D₄ is NR⁹⁰². In other compounds,each of D₁ and D₂ is N, D₃ is CR⁹⁰¹, and D₄ is NR⁹⁰². In still othercompounds, each of D₁ and D₃ is, independently, CR⁹⁰¹, D₂ is N, and D₄is NR⁹⁰². In further other compounds, D₁ is N, each of D₂ and D₃,independently, is CR⁹⁰¹ and D₄ is O or S.

For example, X is

In the above structure, each of E₁, E₂, and E₄, independently, is CR⁹⁰³or N, provided that at least one of E₁, E₂, and E₄ is N. E₃ is O, S, orNR⁹⁰⁴. Each R⁹⁰³ and R⁹⁰⁴, independently, is Q₇-T₇, wherein Q₇ is a bondor C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —C(O)R_(n), —C(O)OR_(n),—C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in whicheach of R_(n) and R_(r), independently is H or R_(S10), each of R_(S9)and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl,or R_(n) and R_(r), together with the N atom to which they are attached,form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, E₁ is N, each of E₂ and E₄,independently, is CR⁹⁰³, and E₃ is NR⁹⁰⁴. In other compounds, each of E₁and E₄, independently, is CR⁹⁰³, E₂ is N, and E₃ is NR⁹⁰⁴. In stillother compounds, each of E₁ and E₂, independently, is CR⁹⁰³, E₃ isNR⁹⁰⁴, and E₄ is N. In further other compounds, each of E₁ and E₂,independently, is CR⁹⁰³, E₃ is O, and E₄ is N.

For example, X is

In the above structure, G₁ is O, S, or NR⁹⁰⁷. Each of G₂, G₃, and G₄,independently, is N or CR⁹⁰⁸, provided that at least one of G₂, G₃, andG₄ is N. Each of R⁹⁰⁵, R⁹⁰⁶, R⁹⁰⁷, and R⁹⁰⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, G₁ is NR⁹⁰⁷, G₂ is CR⁹⁰⁸, and each of G₃and G₄ is N. In other compounds, G₁ is NR⁹⁰⁷, each of G₂ and G₄,independently, is CR⁹⁰⁸, and G₃ is N. In still other compounds, G₁ isNR⁹⁰⁷, each of G₂ and G₄ is N, and G₃ is CR⁹⁰⁸. In further othercompounds, G₁ is NR⁹⁰⁷, G₂ is N, and each of G₃ and G₄, independently,is CR⁹⁰⁸.

For example, X is

In the above structure, each of J₁, J₂, J₃, and J₄, independently, is Nor CR⁹¹¹, provided that at least one of J₁, J₂, J₃, and J₄ is N. Each ofR⁹⁰⁹, R⁹¹⁰, and R⁹¹¹, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), inwhich each of R_(n) and R_(r), independently is H or R_(S10), each ofR_(S9) and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-memberedheteroaryl, or R_(n) and R_(r), together with the N atom to which theyare attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or1 additional heteroatom, and each of R_(S9), R_(S10), and the 4 to12-membered heterocycloalkyl ring formed by R_(n) and R_(r), isoptionally substituted with one or more -Q₈-T₈, wherein Q₈ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₈ is selected from the group consistingof halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s),COOR_(s), —S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s)and R_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or-Q₇-T₇ is oxo; or any two neighboring -Q₇-T₇ together with the atoms towhich they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl. In some compounds, each of J₁ is N and each ofJ₂, J₃, and J₄, independently, is CR⁹¹¹.

For example, X is

In the above structure, each of K₁, K₂, K₃, and K₄, independently, is Nor CR⁹¹⁴, provided that at least one of K₁, K₂, K₃, and K₄ is N. Each ofR⁹¹², R⁹¹³, and R⁹¹⁴, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, K₁ is N and each of K₂, K₃, and K₄,independently, is CR⁹¹⁴. In other compounds, each of K₁ and K₄ is N andeach of K₂ and K₃, independently, is CR⁹¹⁴.

For example, X is

In the above structure, each of U₁, U₃, and U₄, independently, is N orCR⁹¹⁷, provided that at least one of U₁, U₃, and U₄ is N. U₂ is O, S, orNR⁹¹⁸. Each of R⁹¹⁵, R⁹¹⁶, R⁹¹⁷, and R⁹¹⁸, independently, is -Q₇-T₇,wherein Q₇ is a bond or C₁-C₃ alkyl linker each optionally substitutedwith halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n),—NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or Q₇-T₇ is oxo;or any two neighboring -Q₇-T₇ together with the atoms to which they areattached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl. In some compounds, U₁ is N, U₂ is NR⁹¹⁸ and each of U₃ andU₄, independently, is CR⁹¹⁷.

For example, X is

In the above structure, each of V₁ and V₂, independently, is N or CR⁹¹⁹,provided that at least one of V₁ and V₂ is N. V₃ is O, S, or NR⁹²⁰. Eachof V₄, V₅, and V₆ is O, S, or NR⁹²¹, or CR⁹²²R⁹²³. Each of R⁹¹⁹, R⁹²⁰,R⁹²¹, R⁹²², and R⁹²³, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(n),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.

For example, X is imidazol-2-yl, imidazol-4-yl, triazol-3-yl,3H-imidazo[4,5-c]pyridin-7-yl, 1H-benzo[d]imidazol-4-yl,1H-indazol-7-yl, isoxazol-3-yl, thiazol-2-yl,1H-pyrazolo[4,3-c]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-c]pyrimidin-8-yl,1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-7-yl,1,4,6,7-tetrahydropyrano[3,4-]imidazol-7-yl, or4,5,6,7-tetrahydro-1H-benzo[d]imidazol-4-yl.

The compounds of this invention also include those of Formula (II) orpharmaceutically acceptable salts thereof:

wherein,

Z₁ is N or CR^(7′),

Z₂ is N or CR^(2′), provided that when Z₁ is N, Z₂ is N,

R^(1′) is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or —(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or —(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₆-C₁₀)bicycloalkyl, unsubstituted or substitutedheterocycloalkyl or —(C₂-C₈)alkenyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl or —(C₂-C₈)alkenyl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl or —(C₂-C₈)alkenyl, —COR^(a′), —CO₂R^(a′),—CONR^(a′)R^(b′), —CONR^(a′)NR^(a′)R^(b′);

R^(2′) is hydrogen, (C₁-C₈)alkyl, trifluoromethyl, alkoxy, or halo, inwhich said (C₁-C₈)alkyl is optionally substituted with one to two groupsselected from amino and (C₁-C₃)alkylamino;

R^(7′) is hydrogen, (C₁-C₃)alkyl, or alkoxy;

R^(3′) is hydrogen, (C₁-C₈)alkyl, cyano, trifluoromethyl,—NR^(a′)R^(b′), or halo;

R^(6′) is selected from the group consisting of hydrogen, halo,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—CONR^(a′)NR^(a′)R^(b′), —SR^(a′), —SOR^(a′), —SO₂R^(a′),—SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′),—NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)OR^(a′), —OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′);

wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom the group consisting of —O(C₁-C₆)alkyl(R^(c′))₁₋₂,—S(C₁-C₆)alkyl(R^(c′))₁₋₂, —(C₁-C₆)alkyl(R^(c′))₁₋₂,—(C₁-C₈)alkyl-heterocycloalkyl, (C₃-C₈)cycloalkyl-heterocycloalkyl,halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—OR^(a′), —OC(O)R^(a′), OC(O)NR^(a′)R^(b′), heterocycloalkyl, aryl,heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

wherein any aryl or heteroaryl moiety of said aryl, heteroaryl,aryl(C₁-C₄)alkyl, or heteroaryl(C₁-C₄)alkyl is optionally substituted by1, 2 or 3 groups independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—OR^(a′), —OC(O)R^(a′), and —OC(O)NR^(a′)R^(b′);

R^(a′) and R^(b′) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

each R^(c′) is independently (C₁-C₄)alkylamino, —NR^(a′)SO2R^(b′),—SO₂R^(a′), —NR^(a′)C(O)OR^(a′), —NR^(a′)R^(b′), or —CO₂R^(a′);

X is a monocyclic or bicyclic 5 to 10-membered saturated, unsaturated,or aromatic ring containing 2-4 heteroatom ring members and optionallysubstituted with one or more -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n),—C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in whicheach of R_(n) and R_(r), independently is H or R_(S10), each of R_(S9)and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl,or R_(n) and R_(r), together with the N atom to which they are attached,form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl; and

n is 0, 1, 2, 3, 4, or 5.

Subgroup A of Formula (II)

R^(1′) is selected from the group consisting of (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R^(2′) is hydrogen, (C₁-C₈)alkyl, trifluoromethyl, alkoxy, or halo, inwhich said (C₁-C₈)alkyl is optionally substituted with one to two groupsselected from amino and (C₁-C₃)alkylamino;

R^(7′) is hydrogen, (C₁-C₃)alkyl, or alkoxy;

R^(3′) is selected from the group consisting of hydrogen, (C₁-C₈)alkyl,cyano, trifluoromethyl, —NR^(a′)R^(b′), and halo;

R^(6′) is selected from the group consisting of hydrogen, halo, cyano,trifluoromethyl, amino, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl; aryl,heteroaryl, acylamino; (C₂-C₈)alkynyl, arylalkynyl, heteroarylalkynyl;—SO₂R^(a′); —SO₂NR^(a′)R^(b′) and —NR^(a′)SO₂R^(b′); wherein any(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)alkynyl, arylalkynyl,heteroarylalkynyl group is optionally substituted by 1, 2 or 3 groupsindependently selected from —O(C₁-C₆)alkyl(R^(c′))₁₋₂,—S(C₁-C₆)alkyl(R^(c′))₁₋₂, —(C₁-C₆)alkyl(R^(c′))₁₋₂,—(C₁-C₈)alkyl-heterocycloalkyl, (C₃-C₈)cycloalkyl-heterocycloalkyl,halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′), heterocycloalkyl, aryl,heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

R^(a′) and R^(b′) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring. An aryl or heteroaryl group in this particular subgroupA is selected independently from the group consisting of furan,thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole,thiadiazole, triazole, tetrazole, benzofuran, benzothiophene,benzoxazole, benzothiazole, phenyl, pyridine, pyridazine, pyrimidine,pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline,quinoxaline, and naphthyridine or another aryl or heteroaryl group asfollows:

wherein in (1),

A is O, NH, or S; B is CH or N, and C is hydrogen or C₁-C₈ alkyl; or

wherein in (2),

D is N or C optionally substituted by hydrogen or C₁-C₈ alkyl; or

wherein in (3),

E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4),

J is O, S or CO; or

wherein in (5),

Q is CH or N;

M is CH or N; and

L/(5) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,—COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —CONR^(a′)NR^(a′)R^(b′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′), or—OR^(a′),

wherein any (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl group is optionallysubstituted by 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SR^(a′), —SOR^(a′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′), and—OC(O)NR^(a′)R^(b′); wherein R^(a′) and R^(b′) are defined as above; or

wherein in (6),

L/(6) is NH or CH₂; or

wherein in (7),

M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,heterocycloalkyl, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—CONR^(a′)NR^(a′)R^(b′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),NR^(a′)NR^(a′)R^(b′), —NR^(a′)NR^(a′)C(O)R^(b′),—NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′), or —OR^(a′),

wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, or heterocycloalkyl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—SR^(a′), —SOR^(a′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro,—NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′),—NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—OR^(a′), —OC(O)R^(a′), and —OC(O)NR^(a′)R^(b′); wherein R^(a′) andR^(b′) are defined as above; or

wherein in (8),

P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2; or

wherein in (9),

S/(9) and T/(9) are C, or S/(9) is C and T/(9) is N, or S/(9) is N andT/(9) is C;

R is hydrogen, amino, methyl, trifluoromethyl, or halo;

U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SO₂R^(a′),—SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —OR^(a′), or 4-(1H-pyrazol-4-yl),

wherein any (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl group is optionallysubstituted by 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SR^(a′), SOR^(a′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′), and—OC(O)NR^(a′)R^(b′); wherein R^(a′) and R^(b′) are defined as above.

Subgroup B of Formula (II)

R^(1′) is (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, or heterocycloalkyl;

R^(2′) is hydrogen, (C₁-C₃)alkyl, or halo, in which said (C₁-C₃)alkyl isoptionally substituted with one to two groups selected from amino and(C₁-C₃)alkylamino;

R^(7′) is hydrogen, (C₁-C₃)alkyl, or alkoxy;

R^(3′) is hydrogen, (C₁-C₈)alkyl or halo;

R^(6′) is hydrogen, halo, cyano, trifluoromethyl, amino, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, aryl, heteroaryl, acylamino; (C₂-C₈)alkynyl,arylalkynyl, heteroarylalkynyl, —SO₂R^(a′), —SO₂NR^(a′)R^(b′), or—NR^(a′)SO₂R^(b);

wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)alkynyl,arylalkynyl, or heteroarylalkynyl group is optionally substituted by 1,2 or 3 groups independently selected from halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano,—COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SR^(a′), —SOR^(a′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′),—OC(O)NR^(a′)R^(b′), heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

R^(a′) and R^(if) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinsaid (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl groupis optionally substituted by 1, 2 or 3 groups independently selectedfrom halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a′) and R^(b′) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring. Aryl and heteroaryl in this definition are selectedfrom the group consisting of furan, thiophene, pyrrole, oxazole,thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole,tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine,quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine or acompound of another aryl or heteroaryl group as follows:

wherein in (1),

A is O, NH, or S; B is CH or N, and C is hydrogen or C₁-C₈ alkyl; or

wherein in (2),

D is N or C optionally substituted by hydrogen or C₁-C₈ alkyl; or

wherein in (3),

E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4),

J is O, S or CO; or

wherein in (5),

Q is CH or N;

M is CH or N; and

L/(5) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,—COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —CONR^(a′)NR^(a′)R^(b′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′), or—OR^(a′),

wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, group is optionallysubstituted by 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SR^(a′), —SOR^(a′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′),NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′), and—OC(O)NR^(a′)R^(b′),

wherein R^(a′) and R^(b′) are defined as above; or

wherein in (6),

L/(6) is NH or CH₂; or

wherein in (7),

M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,heterocycloalkyl, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′),—CONR^(a′)NR^(a′)R^(b′), —SO₂R^(a′), —SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), —NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′),—NR^(a′)NR^(a′)R^(b′), —NR^(a′)NR^(a′)C(O)R^(b′),—NR^(a′)NR^(a′)C(O)NR^(a′)R^(b′), or —OR^(a′),

wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl group isoptionally substituted by 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SR^(a′), —SOR^(a′),—SO₂R^(a′), —SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′),—NR^(a′)C(O)R^(b′), NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′), and—OC(O)NR^(a′)R^(b′); wherein R^(a′) and R^(b′) are defined as above; or

wherein in (8),

P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2; or

wherein in (9),

S/(9) and T/(9) are C, or S/(9) is C and T/(9) is N, or S/(9) is N andT/(9) is C;

R is hydrogen, amino, methyl, trifluoromethyl, halo;

U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a′), —CONR^(a′)R^(b′), —SO₂R^(a′),—SO₂NR^(a′)R^(b′), —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)SO₂R^(b′), —NR^(a′)SO₂NR^(a′)R^(b′), —NR^(a′)NR^(a′)R^(b′),—NR^(a′)NR^(a′)C(O)R^(b′), —OR^(a′), or 4-(1H-pyrazol-4-yl),

wherein any (C₁-C₈)alkyl, or (C₃-C₈)cycloalkyl group is optionallysubstituted by 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a′), —CO₂R^(a′), —CONR^(a′)R^(b′), —SOR^(a′), —SO₂R^(a′),—SO₂NR^(a′)R^(b′), nitro, —NR^(a′)R^(b′), —NR^(a′)C(O)R^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)C(O)OR^(a′), —NR^(a′)SO₂R^(b′),—NR^(a′)SO2NR^(a′)R^(b′), —OR^(a′), —OC(O)R^(a′), and—OC(O)NR^(a′)R^(b′), wherein R^(a′) and R^(b′) are defined as above.

Subgroup C of Formula (II)

R^(1′) is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,(1-methylethyl)cyclopropyl, 1,1-dioxo-tetrahydrothiophene-3-yl,1-Me-piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl,N,N-dimethyl-1-propanaminyl, benzyl, or 4-pyridyl;

R^(2′) is hydrogen, (C₁-C₃)alkyl, or halo, in which said (C₁-C₃)alkyl isoptionally substituted with one to two groups selected from amino and(C₁-C₃)alkylamino;

R^(7′) is hydrogen, (C₁-C₃)alkyl, or alkoxy;

R^(3′) is H, methyl, or Br; and

R^(6′) is methyl, bis(1,1-dimethylethyl), bis(1-methylethyl),cyclopropyl, propyl, dimethylamino, ethyl amino, (2-hydroxyethyl)amino,2-propen-1-yl amino, 1-piperazinyl, 1-piperidinyl, 4-morpholinyl,4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenyl amino,(phenylmethyl)amino, (4-pyridinylmethyl)amino,[2-(2-pyridinylamino)ethyl]amino, 2-(dimethylamino)ethyl]amino,4-pyridinylamino, 4-(aminocarbonyl)phenyl]amino,3-hydroxy-3-methyl-1-butyn-1-yl, 4-pyridinylethynyl, phenylethynyl,2-furanyl, 3-thienyl; 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-indazol-6-yl,3-methyl-1H-indazol-5-yl, 1H-1,2,3-benzotriazol-5-yl,2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,2-oxo-2,3-dihydro-1H-indol-6-yl, 2,1,3-benzoxadiazol-5-yl,2-amino-6-quinazolinyl, 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl,2-amino-5-pyrimidinyl, 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl,phenyl, 2-methylphenyl, 2-nitrophenyl, 2-phenylethyl, 3-aminophenyl,4-aminophenyl, 4-chlorophenyl, fluorophenyl, 4-(methyloxy)phenyl,3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 4-(aminocarbonyl)phenyl,4-(1H-pyrazol-4-yl)phenyl, 4-(aminosulfonyl)phenyl,4-(methylsulfonyl)phenyl, 4-[(dimethylamino)sulfonyl]phenyl,4-[(methylamino)carbonyl]phenyl, 4-[(methylamino)sulfonyl]phenyl,4-[(methylsulfonyl)amino]phenyl, 3-pyridinyl, 4-pyridinyl,2-(4-morpholinyl)-4-pyridinyl, 2-amino-4-pyridinyl,5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl,5-[(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl,5-[(phenylsulfonyl)amino]-3-pyridinyl,6-(4-methyl-1-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl,6-(acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl,6-(methyloxy)-3-pyridinyl, 6-[(methylamino)carbonyl]-3-pyridinyl,6-[(methylamino)sulfonyl]-3-pyridinyl, 6-methyl-3-pyridinyl, or4-pyridinyloxy.

Representative compounds of the present invention include compoundslisted in Tables 1-3. In Table 1, X₁ through X₄ and Y₁ through Y₃ are asdefined herein for Formula (I). In Table 2, except for R₆ and R₇,variables such as X₂ through X₄, Y₁, Y₃R₁, and R₂ are as defined hereinfor Formula (I). In Table 3, R′″ is T₅, —C(O)T₅, or S(O)₂T₅, and theother variables such as X₂ through X₄, Y₁, Y₃, R₁, R₂, R₆ and T₅ are asdefined herein for Formula (I).

TABLE 1

Structure of Z

TABLE 2

Structure of R₆

TABLE 3

Structure of R₇ sec-butyl cyclopentyl isopropyl

For example, compounds having Z from Table 1 also have R₆ from Table 2and/or have R₇ from Table 3.

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

As used herein, the term “cycloalkyl” refers to a saturated orunsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused,bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g.,C₃-C₁₀). Examples of cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.The term “heterocycloalkyl” refers to a saturated or unsaturatednonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused,bridged, or spiro rings), or 11-14 membered tricyclic ring system(fused, bridged, or spiro rings) having one or more heteroatoms (such asO, N, S, or Se), unless specified otherwise. Examples ofheterocycloalkyl groups include, but are not limited to, piperidinyl,piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl,indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl,thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl,dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl,1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl,1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl,1-azaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl,7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-yl,3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl, and the like.

The term “optionally substituted alkyl” refers to unsubstituted alkyl oralkyl having designated substituents replacing one or more hydrogenatoms on one or more carbons of the hydrocarbon backbone. Suchsubstituents can include, for example, alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

An “arylalkyl” or an “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl(benzyl)). An “alkylaryl” moiety is an arylsubstituted with an alkyl (e.g., methylphenyl).

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅or C₆ straight chain (linear) saturated divalent aliphatic hydrocarbongroups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbongroups. For example, C₁-C₆ alkyl linker is intended to include C₁, C₂,C₃, C₄, C₅ and C₆ alkyl linker groups. Examples of alkyl linker include,moieties having from one to six carbon atoms, such as, but not limitedto, methyl (—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—).

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includes straightchain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenylgroups.

In certain embodiments, a straight chain or branched alkenyl group hassix or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straightchain, C₃-C₆ for branched chain). The twin “C₂-C₆” includes alkenylgroups containing two to six carbon atoms. The twin “C₃-C₆” includesalkenyl groups containing three to six carbon atoms.

The term “optionally substituted alkenyl” refers to unsubstitutedalkenyl or alkenyl having designated substituents replacing one or morehydrogen atoms on one or more hydrocarbon backbone carbon atoms. Suchsubstituents can include, for example, alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. Incertain embodiments, a straight chain or branched alkynyl group has sixor fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain,C₃-C₆ for branched chain). The term “C₂-C₆” includes alkynyl groupscontaining two to six carbon atoms. The term “C₃-C₆” includes alkynylgroups containing three to six carbon atoms.

The term “optionally substituted alkynyl” refers to unsubstitutedalkynyl or alkynyl having designated substituents replacing one or morehydrogen atoms on one or more hydrocarbon backbone carbon atoms. Suchsubstituents can include, for example, alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkyl carbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substitutedcycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both theunsubstituted moieties and the moieties having one or more of thedesignated substituents. For example, substituted heterocycloalkylincludes those substituted with one or more alkyl groups, such as2,2,6,6-tetramethyl-piperidinyl and2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

“Aryl” includes groups with aromaticity, including “conjugated,” ormulticyclic systems with at least one aromatic ring and do not containany heteroatom in the ring structure. Examples include phenyl, benzyl,1,2,3,4-tetrahydronaphthalenyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, except havingfrom one to four heteroatoms in the ring structure, and may also bereferred to as “aryl heterocycles” or “heteroaromatics.” As used herein,the term “heteroaryl” is intended to include a stable 5-, 6-, or7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independentlyselected from the group consisting of nitrogen, oxygen and sulfur. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or other substituents, as defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and thelike.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, quinoline, isoquinoline, naphthrydine, indole,benzofuran, purine, benzofuran, deazapurine, indolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can besubstituted at one or more ring positions (e.g., the ring-forming carbonor heteroatom such as N) with such substituents as described above, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroarylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. Carbocycle includes cycloalkyl and aryl. For example, aC₃-C₁₄ carbocycle is intended to include a monocyclic, bicyclic ortricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbonatoms. Examples of carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are alsoincluded in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0]bicyclodecane and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” or “heterocyclic group” includes any ringstructure (saturated, unsaturated, or aromatic) which contains at leastone ring heteroatom (e.g., N, O or S). Heterocycle includesheterocycloalkyl and heteroaryl. Examples of heterocycles include, butare not limited to, morpholine, pyrrolidine, tetrahydrothiophene,piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, andtetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “azole,” as used herein, refers to a class of five-memberednitrogen heterocyclic ring compounds containing at least anothernon-carbon atom of nitrogen, sulfur, or oxygen.

The term “substituted,” as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is oxo or keto (i.e., ═O), then 2 hydrogen atoms onthe atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituentor formula for a compound, its definition at each occurrence isindependent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R moieties, thenthe group may optionally be substituted with up to two R moieties and Rat each occurrence is selected independently from the definition of R.Also, combinations of substituents and/or variables are permissible, butonly if such combinations result in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo andiodo. The term “perhalogenated” generally refers to a moiety wherein allhydrogen atoms are replaced by halogen atoms. The term “haloalkyl” or“haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or morehalogen atoms.

The term “carbonyl” includes compounds and moieties which contain acarbon connected with a double bond to an oxygen atom. Examples ofmoieties containing a carbonyl include, but are not limited to,aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term “carboxyl” refers to COOH or its C₁-C₆ alkyl ester.

“Acyl” includes moieties that contain the acyl radical (R—C(O)—) or acarbonyl group. “Substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by, for example, alkyl groups,alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Aroyl” includes moieties with an aryl or heteroaromatic moiety bound toa carbonyl group. Examples of aroyl groups include phenylcarboxy,naphthyl carboxy, etc.

“Alkoxyalkyl,” “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkylgroups, as described above, wherein oxygen, nitrogen, or sulfur atomsreplace one or more hydrocarbon backbone carbon atoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups or alkoxyl radicals include, but are notlimited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxygroups. Examples of substituted alkoxy groups include halogenated alkoxygroups. The alkoxy groups can be substituted with groups such asalkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, di arylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ether” or “alkoxy” includes compounds or moieties whichcontain an oxygen bonded to two carbon atoms or heteroatoms. Forexample, the term includes “alkoxyalkyl,” which refers to an alkyl,alkenyl, or alkynyl group covalently bonded to an oxygen atom which iscovalently bonded to an alkyl group.

The term “ester” includes compounds or moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc.

The term “thioalkyl” includes compounds or moieties which contain analkyl group connected with a sulfur atom. The thioalkyl groups can besubstituted with groups such as alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The term “thioether” includes moieties which contain a sulfur atombonded to two carbon atoms or heteroatoms. Examples of thioethersinclude, but are not limited to alkthioalkyls, alkthioalkenyls, andalkthioalkynyls. The term “alkthioalkyls” include moieties with analkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bondedto an alkyl group. Similarly, the term “alkthioalkenyls” refers tomoieties wherein an alkyl, alkenyl or alkynyl group is bonded to asulfur atom which is covalently bonded to an alkenyl group; andalkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynylgroup is bonded to a sulfur atom which is covalently bonded to analkynyl group.

As used herein, “amine” or “amino” refers to —NH₂. “Alkylamino” includesgroups of compounds wherein the nitrogen of —NH₂ is bound to at leastone alkyl group. Examples of alkylamino groups include benzylamino,methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includesgroups wherein the nitrogen of —NH₂ is bound to two alkyl groups.Examples of dialkylamino groups include, but are not limited to,dimethylamino and diethylamino. “Arylamino” and “diarylamino” includegroups wherein the nitrogen is bound to at least one or two aryl groups,respectively. “Aminoaryl” and “aminoaryloxy” refer to aryl and aryloxysubstituted with amino. “Alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group which is bound to at least onealkyl group and at least one aryl group. “Alkaminoalkyl” refers to analkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is alsobound to an alkyl group. “Acylamino” includes groups wherein nitrogen isbound to an acyl group. Examples of acylamino include, but are notlimited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureidogroups.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl or alkynyl groups bound to an amino group whichis bound to the carbon of a carbonyl or thiocarbonyl group. It alsoincludes “arylaminocarboxy” groups that include aryl or heteroarylmoieties bound to an amino group that is bound to the carbon of acarbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”,“alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy”include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties,respectively, are bound to a nitrogen atom which is in turn bound to thecarbon of a carbonyl group. Amides can be substituted with substituentssuch as straight chain alkyl, branched alkyl, cycloalkyl, aryl,heteroaryl or heterocycle. Substituents on amide groups may be furthersubstituted.

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to affordother compounds of the present invention. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the present inventioncan be converted to N-hydroxy or N-alkoxy compounds. For example,N-hydroxy compounds can be prepared by oxidation of the parent amine byan oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent invention includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like, it being understood that not all isomers mayhave the same level of activity. In addition, a crystal polymorphism maybe present for the compounds represented by the formula. It is notedthat any crystal form, crystal form mixture, or anhydride or hydratethereof is included in the scope of the present invention.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers.” Stereoisomers that are notmirror images of one another are termed “diastereoisomers,” andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture.”

A carbon atom bonded to four nonidentical substituents is termed a“chiral center.”

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture.” When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Calm et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds or a cycloalkyl linker (e.g.,1,3-cyclobutyl). These configurations are differentiated in their namesby the prefixes cis and trans, or Z and E, which indicate that thegroups are on the same or opposite side of the double bond in themolecule according to the Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present invention maybe depicted as different chiral isomers or geometric isomers. It shouldalso be understood that when compounds have chiral isomeric or geometricisomeric forms, all isomeric forms are intended to be included in thescope of the present invention, and the naming of the compounds does notexclude any isomeric forms, it being understood that not all isomers mayhave the same level of activity.

Furthermore, the structures and other compounds discussed in thisinvention include all atropic isomers thereof, it being understood thatnot all atropic isomers may have the same level of activity. “Atropicisomers” are a type of stereoisomer in which the atoms of two isomersare arranged differently in space. Atropic isomers owe their existenceto a restricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques, ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solutions wheretautomerization is possible, a chemical equilibrium of the tautomerswill be reached. The exact ratio of the tautomers depends on severalfactors, including temperature, solvent and pH. The concept of tautomersthat are interconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), imine-enamine andenamine-enamine.

It is to be understood that the compounds of the present invention maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present invention, and the naming ofthe compounds does not exclude any tautomer form. It will be understoodthat certain tautomers may have a higher level of activity than others.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility.

Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Crystalpolymorphs of the compounds can be prepared by crystallization underdifferent conditions.

The compounds of any Formula described herein include the compoundsthemselves, as well as their salts, and their solvates, if applicable. Asalt, for example, can be formed between an anion and a positivelycharged group (e.g., amino) on an azole compound. Suitable anionsinclude chloride, bromide, iodide, sulfate, bisulfate, sulfamate,nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate,glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate,tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, andacetate (e.g., trifluoroacetate). The term “pharmaceutically acceptableanion” refers to an anion suitable for forming a pharmaceuticallyacceptable salt. Likewise, a salt can also be formed between a cationand a negatively charged group (e.g., carboxylate) on an azole compound.Suitable cations include sodium ion, potassium ion, magnesium ion,calcium ion, and an ammonium cation such as tetramethylammonium ion. Theazole compounds also include those salts containing quaternary nitrogenatoms.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have acommon core structure, and are substituted with various groups asdescribed herein. For example, all of the compounds represented byFormula (I) are azole compounds, and have Formula (I) as a common core.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres include,but are not limited to, acyl sulfonimides, tetrazoles, sulfonates andphosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176,1996.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The present invention provides methods for the synthesis of thecompounds of any of the Formulae described herein. The present inventionalso provides detailed methods for the synthesis of various disclosedcompounds of the present invention according to the following schemes asshown in the Examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups, therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt thereof.

Compounds of the present invention can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001;Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999; R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieserand M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995), incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentinvention.

Compounds of the present invention can be conveniently prepared by avariety of methods familiar to those skilled in the art or thosedescribed in WO 2012142504, WO 2012142513 and WO 2012118812, which areincorporated herein by reference. The compounds of this invention withany of the Formulae described herein may be prepared according to theprocedures illustrated in Schemes 1-4 below, from commercially availablestarting materials or starting materials which can be prepared usingliterature procedures. The R groups (such as R₁, R₂, R₃, R₄, R₆, R₇, R₈,and R₁₂) in Schemes 1-4 are as defined in any Formula described herein,unless otherwise specified.

One of ordinary skill in the art will note that, during the reactionsequences and synthetic schemes described herein, the order of certainsteps may be changed, such as the introduction and removal of protectinggroups.

One of ordinary skill in the art will recognize that certain groups mayrequire protection from the reaction conditions via the use ofprotecting groups. Protecting groups may also be used to differentiatesimilar functional groups in molecules. A list of protecting groups andhow to introduce and remove these groups can be found in Greene, T. W.,Wuts, P. G. M., Protective Groups in Organic Synthesis, 3^(rd) edition,John Wiley & Sons: New York, 1999.

Preferred protecting groups include, but are not limited to:

For a hydroxyl moiety: TBS, benzyl, THP, Ac

For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allylester

For amines: Cbz, BOC, DMB

For diols: Ac (×2) TBS (×2), or when taken together acetonides

For thiols: Ac

For benzimidazoles: SEM, benzyl, PMB, DMB

For aldehydes: di-alkyl acetals such as dimethoxy acetal or diethylacetyl.

In the reaction schemes described herein, multiple stereoisomers may beproduced. When no particular stereoisomer is indicated, it is understoodto mean all possible stereoisomers that could be produced from thereaction. A person of ordinary skill in the art will recognize that thereactions can be optimized to give one isomer preferentially, or newschemes may be devised to produce a single isomer. If mixtures areproduced, techniques such as preparative thin layer chromatography,preparative HPLC, preparative chiral HPLC, or preparative SFC may beused to separate the isomers.

The following abbreviations are used throughout the specification andare defined below:

-   -   AA ammonium acetate    -   ACN acetonitrile    -   Ac acetyl    -   AcOH acetic acid    -   atm atmosphere    -   aq. Aqueous    -   BID or b.i.d. bis in die (twice a day)    -   tBuOK potassium t-butoxide    -   Bn benzyl    -   BOC tert-butoxy carbonyl    -   BOP        (benzotriazol-1-yloxy)tris(dimethylamino)-phosphoniumhexafluorophosphate    -   Cbz benzyloxy carbonyl    -   CDCl₃ deuterated chloroform    -   CH₂Cl₂ dichloromethane    -   COMU        (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethyl-amino-morpholino-carbenium        hexafluorophosphate    -   d days    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCE 1,2 dichloroethane    -   DCM dichloromethane    -   DEAD Diethyl azodicarboxylate    -   DIAD Diisopropyl azodicarboxylate    -   DiBAL-H diisobutyl aluminium hydride    -   DIPEA N,N-diisopropylethylamine (Hunig's base)    -   DMA Dimethylacetamide    -   DMAP N, N dimethyl-4-aminopyridine    -   DMB 2,4 dimethoxy benzyl    -   DMF N,N-Dimethylformamide    -   DMSO Dimethyl sulfoxide    -   DPPA Diphenylphosphonic azide    -   EA or EtOAc Ethyl acetate    -   EDC or EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide    -   Et₂O diethyl ether    -   ELS Evaporative Light Scattering    -   ESI− Electrospray negative mode    -   ESI+ Electrospray positive mode    -   Et₃N or TEA triethylamine    -   EtOH ethanol    -   FA formic acid    -   FC or FCC Flash chromatography    -   h hours    -   H₂O water    -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HOAT 1-Hydroxy-7-azabenzotriazole    -   HOBt 1-Hydroxybenzotriazole    -   HO-Su N-Hydroxysuccinimide    -   HCl hydrogen chloride or hydrochloric acid    -   HPLC High performance liquid chromatography    -   K₂CO₃ potassium carbonate    -   KHMDs Potassium hexamethyldisilazide    -   LC/MS or LC-MS Liquid chromatography mass spectrum    -   LDA Lithium diisopropylamide    -   LiHMDs Lithium hexamethyldisilazide    -   LG leaving group    -   M Molar    -   m/z mass/charge ratio    -   m-CPBA meta-chloroperbenzoic acid    -   MeCN Acetonitrile    -   MeOD d4-methanol    -   MeI Methyl iodide    -   MS3 Å 3 Å molecular sieves    -   MgSO₄ Magnesium Sulfate    -   min minutes    -   Ms Mesyl    -   MsCl Mesyl chloride    -   MsO Mesylate    -   MS Mass Spectrum    -   MWI microwave irradiation    -   Na₂CO₃ sodium carbonate    -   Na₂SO₄ sodium sulfate    -   NaHCO₃ sodium bicarbonate    -   NaHMDs Sodium hexamethyldisilazide    -   NaOH sodium hydroxide    -   NaHCO₃ sodium bicarbonate    -   Na₂SO₄ sodium sulfate    -   NIS N-iodosuccinimide    -   NMR Nuclear Magnetic Resonance    -   o/n or O/N overnight    -   Pd/C Palladium on carbon    -   Pd(dppf)Cl₂.DCM        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),        complex with dichloromethane    -   PPAA 1-Propanephosphonic acid cyclic anhydride    -   Pd(OH)₂ Palladium dihydroxide    -   PE Petroleum Ether    -   PG protecting group    -   PMB para methoxybenzyl    -   ppm parts per million    -   p.o. per os (oral administration)    -   prep HPLC preparative High Performance Liquid Chromatography    -   prep TLC preparative thin layer chromatography    -   p-TsOH para-toluenesulfonic acid    -   PYBOP (Benzotiazol-1-yloxy)tripyrrolidinophosphonium    -   Hexafluorophosphate    -   QD or q.d. quaque die (once a day)    -   RBF round bottom flask    -   RP-HPLC Reverse phase High Performance liquid chromatography    -   Rt or RT Room temperature    -   SEM (Trimethylsilyl)ethoxymethyl    -   SEMCl (Trimethylsilyl)ethoxymethyl chloride    -   SFC Super critical chromatography    -   SGC silica gel chromatography    -   STAB Sodium triacetoxy borohydride    -   TBAF tetra-n-butylammonium fluoride    -   TBME tert-Butyl methyl ether    -   TEA Triethylamine    -   TFA trifluoroacetic acid    -   TfO triflate    -   THF tetrahydrofuran    -   THP tetrahydropyran    -   TID or t.i.d ter in die (three times a day)    -   TLC thin layer chromatography    -   TMSCl Trimethylsilyl chloride    -   Ts tosyl    -   TsOH tosic acid    -   UV ultraviolet

Scheme 1 shows the synthesis of modified azole-amine following a generalroute that utilizes well-established chemistry. Azole-nitrile (e.g.,2,6-dimethyl-2H-indazole-7-carbonitrile, the synthetic method of whichis shown in Scheme 2; also see Example 1), many of which arecommercially available or can be made by known methods, is reduced to anamine using an appropriate reducing agent, such as Raney-Nickel in thepresence of hydrogen, in a protic solvent, such as methanol containingammonia, at an appropriate temperature, such as 22° C. The obtainedamine compound can be used in the subsequent coupling reaction to makethe desired compounds.

Scheme 2 shows the synthesis of modified pyrazolopyridine analogsfollowing a general route that utilizes well-established chemistry.Condensation of 1H-pyrazol-3-amine with sodium(E)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate in a polar solvent such aswater using a mild acid catalyst such as acetic acid can provide thehydroxyl-pyrazolopyridine (Step 1). The hydroxyl group can then beconverted to a leaving group “X” such as bromide using phosphoryltribromide at elevated temperatures in an appropriate polar solvent suchas acetonitrile to give the bromide (Step 2). Introduction of the R₇ canbe done using an appropriate R₇-LG where LG is a leaving group such asOTs or Br. Subjecting the intermediate to R₇-LG in the presence of amild base such as potassium carbonate in an appropriate polar solventsuch as acetonitrile gives the desired substituted pyrazolopyridine(Step 3). A variety of R₆ substituents can then be introduced usingstandard transition metal-based protocols that rely upon a leaving groupsuch as a bromide as a connection point or through direct SN_(Ar)displacement of the bromide with a nucleophile. The bromide can becombined with an appropriate boronic ester derivative, in the presenceof a mild base and a palladium catalyst in a polar solvent such asdioxane/water, at elevated temperature to give the desiredpyrazolopyridine ester (Step 4). Alternatively, the bromide can becombined with a nucleophile such as an amine in the presence of a mildbase such as potassium carbonate in a polar solvent such as acetone togive the desired pyrazolopyridine ester. The ester moiety can beconverted to an amide using a standard two step protocol. The ester canbe hydrolyzed to the corresponding acid using a suitable base such assodium hydroxide in a polar solvent such as ethanol (Step 5). The acidis then subjected to an amide coupling reaction whereupon theappropriate amine is added along with a suitable amide coupling reagentsuch as PYBOP in a suitable solvent such as DMSO to give the desiredamide (Step 6).

Scheme 3 shows the synthesis of modified indazole analogs following ageneral route that utilizes well-established chemistry. Introduction ofa nitro group to a tolyl compound can be achieved using standardnitration conditions such as nitric acid in sulfuric acid (Step 1). Theacid can be esterified by treatment with an alkylating agent such asmethyliodide in the presence of a base such as sodium carbonate in anappropriate polar solvent such as DMF (Step 2). Reduction of the nitrogroup using an appropriate reducing agent such as iron with an acid suchas ammonium chloride in a protic solvent such as ethanol can provide ananiline (Step 3). Diazotization with an appropriate reagent such assodium nitrite in a polar solvent such as acetic acid can lead tocyclization to provide an indazole (Step 4). It will be apparent to oneskilled in the art that there are multiple ways to synthesize indazoles(J. Org. Chem. 2006, 71, 8166-8172). Introduction of the R₇ to theindazole can be done using an appropriate R₇-LG where LG is a leavinggroup such as OTs or Br. Subjecting the intermediate to R₇-LG in thepresence of a mild base such as cesium carbonate in an appropriate polarsolvent such as DMF can give the desired R₇-substituted indazole ester(Step 5). The ester moiety can be converted to an amide using a standardtwo step protocol. The ester can be hydrolyzed to the corresponding acidusing a suitable base such as sodium hydroxide in a polar solvent suchas ethanol (Step 6). The acid can then reacted with a standard amidecoupling reaction whereupon the appropriate amine can be added alongwith a suitable amide coupling reagent such as PYBOP in a suitablesolvent such as DMSO to give the desired amide (Step 7).

When R₆ is an appropriate group such as bromide or triflate, a varietyof substituents could then be introduced using standard transitionmetal-based protocols. For example, the bromide can be combined with anappropriate boronic ester derivative, in the presence of a mild base anda palladium catalyst in a polar solvent such as dioxane water, atelevated temperature to give the desired indazole (Scheme 4).

A person of ordinary skill in the art will recognize that in the aboveschemes the order of many of the steps are interchangeable.

Compounds of the present invention inhibit the histone methyltransferaseactivity of EZH2 or a mutant thereof and, accordingly, in one aspect ofthe invention, certain compounds disclosed herein are candidates fortreating, or preventing certain conditions and diseases in which EZH2plays a role. The present invention provides methods for treatingconditions and diseases the course of which can be influenced bymodulating the methylation status of histones or other proteins, whereinsaid methylation status is mediated at least in part by the activity ofEZH2. Modulation of the methylation status of histones can in turninfluence the level of expression of target genes activated bymethylation, and/or target genes suppressed by methylation. The methodincludes administering to a subject in need of such treatment, atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, polymorph, solvate, orstereoisomer thereof.

The disorder in which EZH2-mediated protein methylation plays a part canbe cancer or a precancerous condition. The present invention furtherprovides the use of a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof in thetreatment of cancer or pre-cancer the course of which can be influencedby modulating EZH2-mediated protein methylation, or, for the preparationof a medicament useful for the treatment of such cancer or pre-cancer.Exemplary cancers that may be treated include lymphomas, includingnon-Hodgkin's lymphoma, follicular lymphoma (FL) and diffuse largeB-cell lymphoma (DLBCL); melanoma; and leukemia, including CML.Exemplary precancerous condition includes myelodysplastic syndrome (MDS;formerly known as preleukemia).

The present invention also provides methods of protecting against adisorder in which EZH2-mediated protein methylation plays a part in asubject in need thereof by administering a therapeutically effectiveamount of compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, to a subject in need ofsuch treatment. The disorder can be cancer, e.g., cancer in whichEZH2-mediated protein methylation plays a role. The present inventionalso provides the use of compound of the present invention, or apharmaceutically acceptable salt, polymorph, solvate, or stereoisomerthereof, for the preparation of a medicament useful for the preventionof a cell proliferative disorder associated, at least in part, withEZH2-mediated protein methylation.

The compounds of this invention can or may be used to modulate protein(e.g., histone) methylation, e.g., to modulate histone methyltransferaseor histone demethylase enzyme activity. At least some of the compoundsof the invention can be used in vivo or in vitro for modulating proteinmethylation. Histone methylation has been reported to be involved inaberrant expression of certain genes in cancers, and in silencing ofneuronal genes in non-neuronal cells. At least some compounds describedherein are suitable candidates for treating these diseases, i.e., todecrease methylation or restore methylation to roughly its level incounterpart normal cells.

Compounds that are methylation modulators can or may be used formodulating cell proliferation. For example, in some cases excessiveproliferation may be reduced with agents that decrease methylation,whereas insufficient proliferation may be stimulated with agents thatincrease methylation. Accordingly, diseases that may be treated by thecompounds of the invention could include hyperproliferative diseases,such as benign cell growth and malignant cell growth.

As used herein, a “subject” is interchangeable with a “subject in needthereof”, both of which refer to a subject having a disorder in whichEZH2-mediated protein methylation plays a part, or a subject having anincreased risk of developing such disorder relative to the population atlarge. A “subject” includes a mammal. The mammal can be e.g., a human orappropriate non-human mammal, such as primate, mouse, rat, dog, cat,cow, horse, goat, camel, sheep or a pig. The subject can also be a birdor fowl. In one embodiment, the mammal is a human. A subject in needthereof can be one who has been previously diagnosed or identified ashaving cancer or a precancerous condition. A subject in need thereof canalso be one who has (e.g., is suffering from) cancer or a precancerouscondition. Alternatively, a subject in need thereof can be one who hasan increased risk of developing such disorder relative to the populationat large (i.e., a subject who is predisposed to developing such disorderrelative to the population at large). A subject in need thereof can havea precancerous condition. A subject in need thereof can have refractoryor resistant cancer (i.e., cancer that doesn't respond or hasn't yetresponded to treatment). The subject may be resistant at start oftreatment or may become resistant during treatment. In some embodiments,the subject in need thereof has cancer recurrence following remission onmost recent therapy. In some embodiments, the subject in need thereofreceived and failed all known effective therapies for cancer treatment.In some embodiments, the subject in need thereof received at least oneprior therapy. In a preferred embodiment, the subject has cancer or acancerous condition. For example, the cancer is lymphoma, leukemia,melanoma, or rhabdomyosarcoma. Preferably, the lymphoma is non-Hodgkin'slymphoma, follicular lymphoma or diffuse large B-cell lymphoma.Alternatively, the leukemia is chronic myelogenous leukemia (CML). Theprecancerous condition is myelodysplastic syndromes (MDS, formerly knownas preleukemia).

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders thatmay be treated with the compounds of the invention encompass a varietyof conditions wherein cell division is deregulated. Exemplary cellproliferative disorder include, but are not limited to, neoplasms,benign tumors, malignant tumors, pre-cancerous conditions, in situtumors, encapsulated tumors, metastatic tumors, liquid tumors, solidtumors, immunological tumors, hematological tumors, cancers, carcinomas,leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term“rapidly dividing cell” as used herein is defined as any cell thatdivides at a rate that exceeds or is greater than what is expected orobserved among neighboring or juxtaposed cells within the same tissue. Acell proliferative disorder includes a precancer or a precancerouscondition. A cell proliferative disorder includes cancer. The methodsand uses provided herein can be or may be used to treat or alleviate asymptom of cancer or to identify suitable candidates for such purposes.The term “cancer” includes solid tumors, as well as, hematologic tumorsand/or malignancies. A “precancer cell” or “precancerous cell” is a cellmanifesting a cell proliferative disorder that is a precancer or aprecancerous condition. A “cancer cell” or “cancerous cell” is a cellmanifesting a cell proliferative disorder that is a cancer. Anyreproducible means of measurement may be used to identify cancer cellsor precancerous cells. Cancer cells or precancerous cells can beidentified by histological typing or grading of a tissue sample (e.g., abiopsy sample). Cancer cells or precancerous cells can be identifiedthrough the use of appropriate molecular markers.

Exemplary non-cancerous conditions or disorders that may be treatedusing one or more compounds of the present invention include, but arenot limited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreaticfibrosis; hepatic fibrosis; acute and chronic renal disease; irritablebowel syndrome; pyresis; restenosis; cerebral malaria; stroke andischemic injury; neural trauma; Alzheimer's disease; Huntington'sdisease; Parkinson's disease; acute and chronic pain; allergic rhinitis;allergic conjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus.

Exemplary cancers that may be treated using one or more compounds of thepresent invention include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, urinarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodeimaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin's lymphoma, primary central nervous systemlymphoma, Waldenstram macroglobulinemia, medulloblastoma, melanoma,intraocular (eye) melanoma, merkel cell carcinoma, mesotheliomamalignant, mesothelioma, metastatic squamous neck cancer, mouth cancer,cancer of the tongue, multiple endocrine neoplasia syndrome, mycosisfungoides, myelodysplastic syndromes, myelodysplastic myeloproliferativediseases, chronic myelogenous leukemia, acute myeloid leukemia, multiplemyeloma, chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

A “cell proliferative disorder of the hematologic system” is a cellproliferative disorder involving cells of the hematologic system. A cellproliferative disorder of the hematologic system can include lymphoma,leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benignmonoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoidpapulosis, polycythemia vera, chronic myelocytic leukemia, agnogenicmyeloid metaplasia, and essential thrombocythemia. A cell proliferativedisorder of the hematologic system can include hyperplasia, dysplasia,and metaplasia of cells of the hematologic system. In one aspect,compositions of the present invention may be used to treat a cancerselected from the group consisting of a hematologic cancer of thepresent invention or a hematologic cell proliferative disorder of thepresent invention, or used to identify suitable candidates for suchpurposes. A hematologic cancer of the present invention can includemultiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin'slymphoma, childhood lymphomas, and lymphomas of lymphocytic andcutaneous origin), leukemia (including childhood leukemia, hairy-cellleukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chroniclymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenousleukemia, and mast cell leukemia), myeloid neoplasms and mast cellneoplasms.

A “cell proliferative disorder of the lung” is a cell proliferativedisorder involving cells of the lung. Cell proliferative disorders ofthe lung can include all forms of cell proliferative disorders affectinglung cells. Cell proliferative disorders of the lung can include lungcancer, a precancer or precancerous condition of the lung, benigngrowths or lesions of the lung, and malignant growths or lesions of thelung, and metastatic lesions in tissue and organs in the body other thanthe lung. In one aspect, compositions of the present invention may beused to treat lung cancer or cell proliferative disorders of the lung,or used to identify suitable candidates for such purposes. Lung cancercan include malignant lung neoplasms, carcinoma in situ, typicalcarcinoid tumors, and atypical carcinoid tumors. Lung cancer can includesmall cell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”),squamous cell carcinoma, adenocarcinoma, small cell carcinoma, largecell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lungcancer can include “scar carcinoma,” bronchioalveolar carcinoma, giantcell carcinoma, spindle cell carcinoma, and large cell neuroendocrinecarcinoma. Lung cancer can include lung neoplasms having histologic andultrastructual heterogeneity (e.g., mixed cell types).

Cell proliferative disorders of the lung can include all forms of cellproliferative disorders affecting lung cells. Cell proliferativedisorders of the lung can include lung cancer, precancerous conditionsof the lung. Cell proliferative disorders of the lung can includehyperplasia, metaplasia, and dysplasia of the lung. Cell proliferativedisorders of the lung can include asbestos-induced hyperplasia, squamousmetaplasia, and benign reactive mesothelial metaplasia. Cellproliferative disorders of the lung can include replacement of columnarepithelium with stratified squamous epithelium, and mucosal dysplasia.Individuals exposed to inhaled injurious environmental agents such ascigarette smoke and asbestos may be at increased risk for developingcell proliferative disorders of the lung. Prior lung diseases that maypredispose individuals to development of cell proliferative disorders ofthe lung can include chronic interstitial lung disease, necrotizingpulmonary disease, scleroderma, rheumatoid disease, sarcoidosis,interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathicpulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, andHodgkin's disease.

A “cell proliferative disorder of the colon” is a cell proliferativedisorder involving cells of the colon. In one aspect, compositions ofthe present invention may be used to treat colon cancer or cellproliferative disorders of the colon, or used to identify suitablecandidates for such purposes. Colon cancer can include all forms ofcancer of the colon. Colon cancer can include sporadic and hereditarycolon cancers. Colon cancer can include malignant colon neoplasms,carcinoma in situ, typical carcinoid tumors, and atypical carcinoidtumors. Colon cancer can include adenocarcinoma, squamous cellcarcinoma, and adenosquamous cell carcinoma. Colon cancer can beassociated with a hereditary syndrome selected from the group consistingof hereditary nonpolyposis colorectal cancer, familial adenomatouspolyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndromeand juvenile polyposis. Colon cancer can be caused by a hereditarysyndrome selected from the group consisting of hereditary nonpolyposiscolorectal cancer, familial adenomatous polyposis, Gardner's syndrome,Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.

Cell proliferative disorders of the colon can include all forms of cellproliferative disorders affecting colon cells. Cell proliferativedisorders of the colon can include colon cancer, precancerous conditionsof the colon, adenomatous polyps of the colon and metachronous lesionsof the colon. A cell proliferative disorder of the colon can includeadenoma. Cell proliferative disorders of the colon can be characterizedby hyperplasia, metaplasia, and dysplasia of the colon. Prior colondiseases that may predispose individuals to development of cellproliferative disorders of the colon can include prior colon cancer.Current disease that may predispose individuals to development of cellproliferative disorders of the colon can include Crohn's disease andulcerative colitis. A cell proliferative disorder of the colon can beassociated with a mutation in a gene selected from the group consistingof p53, ras, FAP and DCC. An individual can have an elevated risk ofdeveloping a cell proliferative disorder of the colon due to thepresence of a mutation in a gene selected from the group consisting ofp53, ras, FAP and DCC.

A “cell proliferative disorder of the pancreas” is a cell proliferativedisorder involving cells of the pancreas. Cell proliferative disordersof the pancreas can include all forms of cell proliferative disordersaffecting pancreatic cells. Cell proliferative disorders of the pancreascan include pancreas cancer, a precancer or precancerous condition ofthe pancreas, hyperplasia of the pancreas, and dysaplasia of thepancreas, benign growths or lesions of the pancreas, and malignantgrowths or lesions of the pancreas, and metastatic lesions in tissue andorgans in the body other than the pancreas. Pancreatic cancer includesall forms of cancer of the pancreas. Pancreatic cancer can includeductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cellcarcinoma, mucinous adenocarcinoma, osteoclast-like giant cellcarcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassifiedlarge cell carcinoma, small cell carcinoma, pancreatoblastoma, papillaryneoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serouscystadenoma. Pancreatic cancer can also include pancreatic neoplasmshaving histologic and ultrastructual heterogeneity (e.g., mixed celltypes).

A “cell proliferative disorder of the prostate” is a cell proliferativedisorder involving cells of the prostate. Cell proliferative disordersof the prostate can include all forms of cell proliferative disordersaffecting prostate cells. Cell proliferative disorders of the prostatecan include prostate cancer, a precancer or precancerous condition ofthe prostate, benign growths or lesions of the prostate, and malignantgrowths or lesions of the prostate, and metastatic lesions in tissue andorgans in the body other than the prostate. Cell proliferative disordersof the prostate can include hyperplasia, metaplasia, and dysplasia ofthe prostate.

A “cell proliferative disorder of the skin” is a cell proliferativedisorder involving cells of the skin. Cell proliferative disorders ofthe skin can include all forms of cell proliferative disorders affectingskin cells. Cell proliferative disorders of the skin can include aprecancer or precancerous condition of the skin, benign growths orlesions of the skin, melanoma, malignant melanoma and other malignantgrowths or lesions of the skin, and metastatic lesions in tissue andorgans in the body other than the skin. Cell proliferative disorders ofthe skin can include hyperplasia, metaplasia, and dysplasia of the skin.

A “cell proliferative disorder of the ovary” is a cell proliferativedisorder involving cells of the ovary. Cell proliferative disorders ofthe ovary can include all forms of cell proliferative disordersaffecting cells of the ovary. Cell proliferative disorders of the ovarycan include a precancer or precancerous condition of the ovary, benigngrowths or lesions of the ovary, ovarian cancer, malignant growths orlesions of the ovary, and metastatic lesions in tissue and organs in thebody other than the ovary. Cell proliferative disorders of the skin caninclude hyperplasia, metaplasia, and dysplasia of cells of the ovary.

A “cell proliferative disorder of the breast” is a cell proliferativedisorder involving cells of the breast. Cell proliferative disorders ofthe breast can include all forms of cell proliferative disordersaffecting breast cells. Cell proliferative disorders of the breast caninclude breast cancer, a precancer or precancerous condition of thebreast, benign growths or lesions of the breast, and malignant growthsor lesions of the breast, and metastatic lesions in tissue and organs inthe body other than the breast. Cell proliferative disorders of thebreast can include hyperplasia, metaplasia, and dysplasia of the breast.

A cell proliferative disorder of the breast can be a precancerouscondition of the breast. Compositions of the present invention may beused to treat a precancerous condition of the breast. A precancerouscondition of the breast can include atypical hyperplasia of the breast,ductal carcinoma in situ (DCIS), intraductal carcinoma, lobularcarcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer,or carcinoma in situ). A precancerous condition of the breast can bestaged according to the TNM classification scheme as accepted by theAmerican Joint Committee on Cancer (AJCC), where the primary tumor (T)has been assigned a stage of T0 or Tis; and where the regional lymphnodes (N) have been assigned a stage of NO; and where distant metastasis(M) has been assigned a stage of M0.

The cell proliferative disorder of the breast can be breast cancer. Inone aspect, compositions of the present invention may be used to treatbreast cancer, or used to identify suitable candidates for suchpurposes. Breast cancer may include all forms of cancer of the breast.Breast cancer includes all forms of cancer of the breast. Breast cancercan include primary epithelial breast cancers. Breast cancer can includecancers in which the breast is involved by other tumors such aslymphoma, sarcoma or melanoma. Breast cancer can include carcinoma ofthe breast, ductal carcinoma of the breast, lobular carcinoma of thebreast, undifferentiated carcinoma of the breast, cystosarcoma phyllodesof the breast, angiosarcoma of the breast, and primary lymphoma of thebreast. Breast cancer can include Stage I, II, IIIA, IIIB, IIIC and IVbreast cancer. Ductal carcinoma of the breast can include invasivecarcinoma, invasive carcinoma in situ with predominant intraductalcomponent, inflammatory breast cancer, and a ductal carcinoma of thebreast with a histologic type selected from the group consisting ofcomedo, mucinous (colloid), medullary, medullary with lymphcyticinfiltrate, papillary, scirrhous, and tubular. Lobular carcinoma of thebreast can include invasive lobular carcinoma with predominant in situcomponent, invasive lobular carcinoma, and infiltrating lobularcarcinoma. Breast cancer can include Paget's disease, Paget's diseasewith intraductal carcinoma, and Paget's disease with invasive ductalcarcinoma. Breast cancer can include breast neoplasms having histologicand ultrastructual heterogeneity (e.g., mixed cell types).

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph, or solvate thereof, may be used to treat breast cancer,or used to identify suitable candidates for such purposes. A breastcancer that is to be treated can include familial breast cancer. Abreast cancer that is to be treated can include sporadic breast cancer.A breast cancer that is to be treated can arise in a male subject. Abreast cancer that is to be treated can arise in a female subject. Abreast cancer that is to be treated can arise in a premenopausal femalesubject or a postmenopausal female subject. A breast cancer that is tobe treated can arise in a subject equal to or older than 30 years old,or a subject younger than 30 years old. A breast cancer that is to betreated has arisen in a subject equal to or older than 50 years old, ora subject younger than 50 years old. A breast cancer that is to betreated can arise in a subject equal to or older than 70 years old, or asubject younger than 70 years old.

A breast cancer that is to be treated can be typed to identify afamilial or spontaneous mutation in BRCA1, BRCA2, or p53. A breastcancer that is to be treated can be typed as having a HER2/neu geneamplification, as overexpressing HER2/neu, or as having a low,intermediate or high level of HER2/neu expression. A breast cancer thatis to be treated can be typed for a marker selected from the groupconsisting of estrogen receptor (ER), progesterone receptor (PR), humanepidermal growth factor receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met.A breast cancer that is to be treated can be typed as ER-unknown,ER-rich or ER-poor. A breast cancer that is to be treated can be typedas ER-negative or ER-positive. ER-typing of a breast cancer may beperformed by any reproducible means. ER-typing of a breast cancer may beperformed as set forth in Onkologie 27: 175-179 (2004). A breast cancerthat is to be treated can be typed as PR-unknown, PR-rich, or PR-poor. Abreast cancer that is to be treated can be typed as PR-negative orPR-positive. A breast cancer that is to be treated can be typed asreceptor positive or receptor negative. A breast cancer that is to betreated can be typed as being associated with elevated blood levels ofCA 15-3, or CA 27-29, or both.

A breast cancer that is to be treated can include a localized tumor ofthe breast. A breast cancer that is to be treated can include a tumor ofthe breast that is associated with a negative sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with a positive sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with one or more positive axillary lymphnodes, where the axillary lymph nodes have been staged by any applicablemethod. A breast cancer that is to be treated can include a tumor of thebreast that has been typed as having nodal negative status (e.g.,node-negative) or nodal positive status (e.g., node-positive). A breastcancer that is to be treated can include a tumor of the breast that hasmetastasized to other locations in the body. A breast cancer that is tobe treated can be classified as having metastasized to a locationselected from the group consisting of bone, lung, liver, or brain. Abreast cancer that is to be treated can be classified according to acharacteristic selected from the group consisting of metastatic,localized, regional, local-regional, locally advanced, distant,multicentric, bilateral, ipsilateral, contralateral, newly diagnosed,recurrent, and inoperable.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, may be used to treat or prevent acell proliferative disorder of the breast, or to treat or prevent breastcancer, in a subject having an increased risk of developing breastcancer relative to the population at large, or used to identify suitablecandidates for such purposes. A subject with an increased risk ofdeveloping breast cancer relative to the population at large is a femalesubject with a family history or personal history of breast cancer. Asubject with an increased risk of developing breast cancer relative tothe population at large is a female subject having a germ-line orspontaneous mutation in BRCA1 or BRCA2, or both. A subject with anincreased risk of developing breast cancer relative to the population atlarge is a female subject with a family history of breast cancer and agerm-line or spontaneous mutation in BRCA1 or BRCA2, or both. A subjectwith an increased risk of developing breast cancer relative to thepopulation at large is a female who is greater than 30 years old,greater than 40 years old, greater than 50 years old, greater than 60years old, greater than 70 years old, greater than 80 years old, orgreater than 90 years old. A subject with an increased risk ofdeveloping breast cancer relative to the population at large is asubject with atypical hyperplasia of the breast, ductal carcinoma insitu (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS),lobular neoplasia, or a stage 0 growth or lesion of the breast (e.g.,stage 0 or grade 0 breast cancer, or carcinoma in situ).

A breast cancer that is to be treated can histologically gradedaccording to the Scarff-Bloom-Richardson system, wherein a breast tumorhas been assigned a mitosis count score of 1, 2, or 3; a nuclearpleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or3; and a total Scarff-Bloom-Richardson score of between 3 and 9. Abreast cancer that is to be treated can be assigned a tumor gradeaccording to the International Consensus Panel on the Treatment ofBreast Cancer selected from the group consisting of grade 1, grade 1-2,grade 2, grade 2-3, or grade 3.

A cancer that is to be treated can be staged according to the AmericanJoint Committee on Cancer (AJCC) TNM classification system, where thetumor (T) has been assigned a stage of TX, T₁, T1mic, T1a, T1b, T1c, T₂,T₃, T₄, T₄a, T₄b, T₄c, or T₄d; and where the regional lymph nodes (N)have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, orN3c; and where distant metastasis (M) can be assigned a stage of MX, M0,or M1. A cancer that is to be treated can be staged according to anAmerican Joint Committee on Cancer (AJCC) classification as Stage I,Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Acancer that is to be treated can be assigned a grade according to anAJCC classification as Grade GX (e.g., grade cannot be assessed), Grade1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can bestaged according to an AJCC pathologic classification (pN) of pNX, pN0,PN0 (I−), PN0 (I+), PN0 (mol−), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b,PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

A cancer that is to be treated can include a tumor that has beendetermined to be less than or equal to about 2 centimeters in diameter.A cancer that is to be treated can include a tumor that has beendetermined to be from about 2 to about 5 centimeters in diameter. Acancer that is to be treated can include a tumor that has beendetermined to be greater than or equal to about 3 centimeters indiameter. A cancer that is to be treated can include a tumor that hasbeen determined to be greater than 5 centimeters in diameter. A cancerthat is to be treated can be classified by microscopic appearance aswell differentiated, moderately differentiated, poorly differentiated,or undifferentiated. A cancer that is to be treated can be classified bymicroscopic appearance with respect to mitosis count (e.g., amount ofcell division) or nuclear pleiomorphism (e.g., change in cells). Acancer that is to be treated can be classified by microscopic appearanceas being associated with areas of necrosis (e.g., areas of dying ordegenerating cells). A cancer that is to be treated can be classified ashaving an abnormal karyotype, having an abnormal number of chromosomes,or having one or more chromosomes that are abnormal in appearance. Acancer that is to be treated can be classified as being aneuploid,triploid, tetraploid, or as having an altered ploidy. A cancer that isto be treated can be classified as having a chromosomal translocation,or a deletion or duplication of an entire chromosome, or a region ofdeletion, duplication or amplification of a portion of a chromosome.

A cancer that is to be treated can be evaluated by DNA cytometry, flowcytometry, or image cytometry. A cancer that is to be treated can betyped as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cellsin the synthesis stage of cell division (e.g., in S phase of celldivision). A cancer that is to be treated can be typed as having a lowS-phase fraction or a high S-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter is in direct contact with acell, or is close enough to induce a desired biological effect in acell.

As used herein, “candidate compound” refers to a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, that has been or will be tested in one or more in vitro or invivo biological assays, in order to determine if that compound is likelyto elicit a desired biological or medical response in a cell, tissue,system, animal or human that is being sought by a researcher orclinician. A candidate compound is a compound of the present invention,or a pharmaceutically acceptable salt, polymorph or solvate thereof. Thebiological or medical response can be the treatment of cancer. Thebiological or medical response can be treatment or prevention of a cellproliferative disorder. The biological response or effect can alsoinclude a change in cell proliferation or growth that occurs in vitro orin an animal model, as well as other biological changes that areobservable in vitro. In vitro or in vivo biological assays can include,but are not limited to, enzymatic activity assays, electrophoreticmobility shift assays, reporter gene assays, in vitro cell viabilityassays, and the assays described herein.

For example, an in vitro biological assay that can be used includes thesteps of (1) mixing a histone substrate (e.g., an isolated histonesample, an isolated histone peptide representative of human histone H3residues 21-44 containing either an unmodified lysine 27 (H3K27me0) ordimethylated lysine 27 (H3K27me2), or an isolated oligonucleosomesubstrate) with recombinant PRC2 enzymes that include a wild type ormutant EZH2 subunit; (2) adding a compound of the invention to thismixture; (3) adding non-radioactive and ³H-labeled S-Adenosyl methionine(SAM) to start the reaction; (4) adding excessive amount ofnon-radioactive SAM to stop the reaction; (4) washing off the freenon-incorporated ³H-SAM; and (5) detecting the quantity of ³H-labeledhistone substrate by any methods known in the art (e.g., by aPerkinElmer TopCount platereader).

For example, an in vivo study that can be used includes the steps of (1)administering a compound of the invention into a mouse model (such asWSU-DLCL2 xenograft tumor bearing mouse model or KARPAS-422 humandiffused large B-Cell lymphoma mouse xenograft model) at certain levelof dosage for certain periods of time, e.g., 7-28 days; (2) sacrificingthe mouse and isolating the tumor tissue; (3) measuring the tumor volumeand body weight and (4) extracting histone from the tumor tissue formeasuring the histone methylation by ELISA.

As used herein, “monotherapy” refers to the administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with oneof the compound of the present invention, or a pharmaceuticallyacceptable salt, analog or derivative thereof, to a subject in need oftreatment of cancer. Monotherapy may be contrasted with combinationtherapy, in which a combination of multiple active compounds isadministered, preferably with each component of the combination presentin a therapeutically effective amount. Monotherapy with a compound ofthe present invention, or a pharmaceutically acceptable salt, polymorphor solvate thereof, may be more effective than combination therapy ininducing a desired biological effect.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, to alleviate the symptoms or complications of a disease,condition or disorder, or to eliminate the disease, condition ordisorder. The term “treat” can also include treatment of a cell in vitroor an animal model.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, can or may also be used to prevent arelevant disease, condition or disorder, or used to identify suitablecandidates for such purposes. As used herein, “prevent,” or “protectingagainst” describes reducing or eliminating the onset of the symptoms orcomplications of such disease, condition or disorder.

As used herein, the term “alleviate” is meant to describe a process bywhich the severity of a sign or symptom of a disorder is decreased.Importantly, a sign or symptom can be alleviated without beingeliminated. The administration of pharmaceutical compositions of theinvention can or may lead to the elimination of a sign or symptom,however, elimination is not required. Effective dosages should beexpected to decrease the severity of a sign or symptom. For instance, asign or symptom of a disorder such as cancer, which can occur inmultiple locations, is alleviated if the severity of the cancer isdecreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potentialof cancer to transform from a precancerous, or benign, state into amalignant state. Alternatively, or in addition, severity is meant todescribe a cancer stage, for example, according to the TNM system(accepted by the International Union Against Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC)) or by other art-recognizedmethods. Cancer stage refers to the extent or severity of the cancer,based on factors such as the location of the primary tumor, tumor size,number of tumors, and lymph node involvement (spread of cancer intolymph nodes). Alternatively, or in addition, severity is meant todescribe the tumor grade by art-recognized methods (see, National CancerInstitute, www.cancer.gov). Tumor grade is a system used to classifycancer cells in terms of how abnormal they look under a microscope andhow quickly the tumor is likely to grow and spread. Many factors areconsidered when determining tumor grade, including the structure andgrowth pattern of the cells. The specific factors used to determinetumor grade vary with each type of cancer. Severity also describes ahistologic grade, also called differentiation, which refers to how muchthe tumor cells resemble normal cells of the same tissue type (see,National Cancer Institute, www.cancer.gov). Furthermore, severitydescribes a nuclear grade, which refers to the size and shape of thenucleus in tumor cells and the percentage of tumor cells that aredividing (see, National Cancer Institute, www.cancer.gov).

Severity can also describe the degree to which a tumor has secretedgrowth factors, degraded the extracellular matrix, become vascularized,lost adhesion to juxtaposed tissues, or metastasized. Moreover, severitycan describe the number of locations to which a primary tumor hasmetastasized. Finally, severity can include the difficulty of treatingtumors of varying types and locations. For example, inoperable tumors,those cancers which have greater access to multiple body systems(hematological and immunological tumors), and those which are the mostresistant to traditional treatments are considered most severe. In thesesituations, prolonging the life expectancy of the subject and/orreducing pain, decreasing the proportion of cancerous cells orrestricting cells to one system, and improving cancer stage/tumorgrade/histological grade/nuclear grade are considered alleviating a signor symptom of the cancer.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body. But signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

Cancer is a group of diseases that may cause almost any sign or symptom.The signs and symptoms will depend on where the cancer is, the size ofthe cancer, and how much it affects the nearby organs or structures. Ifa cancer spreads (metastasizes), then symptoms may appear in differentparts of the body.

As a cancer grows, it begins to push on nearby organs, blood vessels,and nerves. This pressure creates some of the signs and symptoms ofcancer. If the cancer is in a critical area, such as certain parts ofthe brain, even the smallest tumor can cause early symptoms.

But sometimes cancers start in places where it does not cause anysymptoms until the cancer has grown quite large. Pancreas cancers, forexample, do not usually grow large enough to be felt from the outside ofthe body. Some pancreatic cancers do not cause symptoms until they beginto grow around nearby nerves (this causes a backache). Others growaround the bile duct, which blocks the flow of bile and leads to ayellowing of the skin known as jaundice. By the time a pancreatic cancercauses these signs or symptoms, it has usually reached an advancedstage.

A cancer may also cause symptoms such as fever, fatigue, or weight loss.This may be because cancer cells use up much of the body's energy supplyor release substances that change the body's metabolism. Or the cancermay cause the immune system to react in ways that produce thesesymptoms.

Sometimes, cancer cells release substances into the bloodstream thatcause symptoms not usually thought to result from cancers. For example,some cancers of the pancreas can release substances which cause bloodclots to develop in veins of the legs. Some lung cancers makehormone-like substances that affect blood calcium levels, affectingnerves and muscles and causing weakness and dizziness.

Cancer presents several general signs or symptoms that occur when avariety of subtypes of cancer cells are present. Most people with cancerwill lose weight at some time with their disease. An unexplained(unintentional) weight loss of 10 pounds or more may be the first signof cancer, particularly cancers of the pancreas, stomach, esophagus, orlung.

Fever is very common with cancer, but is more often seen in advanceddisease. Almost all patients with cancer will have fever at some time,especially if the cancer or its treatment affects the immune system andmakes it harder for the body to fight infection. Less often, fever maybe an early sign of cancer, such as with leukemia or lymphoma.

Fatigue may be an important symptom as cancer progresses. It may happenearly, though, in cancers such as with leukemia, or if the cancer iscausing an ongoing loss of blood, as in some colon or stomach cancers.

Pain may be an early symptom with some cancers such as bone cancers ortesticular cancer. But most often pain is a symptom of advanced disease.

Along with cancers of the skin (see next section), some internal cancerscan cause skin signs that can be seen. These changes include the skinlooking darker (hyperpigmentation), yellow (jaundice), or red(erythema); itching; or excessive hair growth.

Alternatively, or in addition, cancer subtypes present specific signs orsymptoms. Changes in bowel habits or bladder function could indicatecancer. Long-teen constipation, diarrhea, or a change in the size of thestool may be a sign of colon cancer. Pain with urination, blood in theurine, or a change in bladder function (such as more frequent or lessfrequent urination) could be related to bladder or prostate cancer.

Changes in skin condition or appearance of a new skin condition couldindicate cancer. Skin cancers may bleed and look like sores that do notheal. A long-lasting sore in the mouth could be an oral cancer,especially in patients who smoke, chew tobacco, or frequently drinkalcohol. Sores on the penis or vagina may either be signs of infectionor an early cancer.

Unusual bleeding or discharge could indicate cancer. Unusual bleedingcan happen in either early or advanced cancer. Blood in the sputum(phlegm) may be a sign of lung cancer. Blood in the stool (or a dark orblack stool) could be a sign of colon or rectal cancer. Cancer of thecervix or the endometrium (lining of the uterus) can cause vaginalbleeding. Blood in the urine may be a sign of bladder or kidney cancer.A bloody discharge from the nipple may be a sign of breast cancer.

A thickening or lump in the breast or in other parts of the body couldindicate the presence of a cancer. Many cancers can be felt through theskin, mostly in the breast, testicle, lymph nodes (glands), and the softtissues of the body. A lump or thickening may be an early or late signof cancer. Any lump or thickening could be indicative of cancer,especially if the formation is new or has grown in size.

Indigestion or trouble swallowing could indicate cancer. While thesesymptoms commonly have other causes, indigestion or swallowing problemsmay be a sign of cancer of the esophagus, stomach, or pharynx (throat).

Recent changes in a wart or mole could be indicative of cancer. Anywart, mole, or freckle that changes in color, size, or shape, or losesits definite borders indicates the potential development of cancer. Forexample, the skin lesion may be a melanoma.

A persistent cough or hoarseness could be indicative of cancer. A coughthat does not go away may be a sign of lung cancer. Hoarseness can be asign of cancer of the larynx (voice box) or thyroid.

While the signs and symptoms listed above are the more common ones seenwith cancer, there are many others that are less common and are notlisted here.

Treating cancer may result in or can result in a reduction in size of atumor. A reduction in size of a tumor may also be referred to as “tumorregression”. Preferably, after treatment, tumor size would be reduced by5% or greater relative to its size prior to treatment; more preferably,tumor size is reduced by 10% or greater; more preferably, reduced by 20%or greater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. The size of a tumor may be measured as a diameter of thetumor.

Treating cancer may result in or can result in a reduction in tumorvolume. Preferably, after treatment, tumor volume would be reduced by 5%or greater relative to its size prior to treatment; more preferably,tumor volume is reduced by 10% or greater; more preferably, reduced by20% or greater; more preferably, reduced by 30% or greater; morepreferably, reduced by 40% or greater; even more preferably, reduced by50% or greater; and most preferably, reduced by greater than 75% orgreater. Tumor volume may be measured by any reproducible means ofmeasurement.

Treating cancer may result in or can result in a decrease in number oftumors. Preferably, after treatment, tumor number would be reduced by 5%or greater relative to number prior to treatment; more preferably, tumornumber is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75%. Number oftumors may be measured by any reproducible means of measurement. Thenumber of tumors may be measured by counting tumors visible to the nakedeye or at a specified magnification. Preferably, the specifiedmagnification is 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer may result in or can result in a decrease in number ofmetastatic lesions in other tissues or organs distant from the primarytumor site. Preferably, after treatment, the number of metastaticlesions would be reduced by 5% or greater relative to number prior totreatment; more preferably, the number of metastatic lesions is reducedby 10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. The number of metastaticlesions may be measured by any reproducible means of measurement. Thenumber of metastatic lesions may be measured by counting metastaticlesions visible to the naked eye or at a specified magnification.Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer may result in or can result in an increase in averagesurvival time of a population of treated subjects in comparison to apopulation receiving carrier alone. Preferably, the average survivaltime would be increased by more than 30 days; more preferably, by morethan 60 days; more preferably, by more than 90 days; and mostpreferably, by more than 120 days. An increase in average survival timeof a population may be measured by any reproducible means. An increasein average survival time of a population may be measured, for example,by calculating for a population the average length of survival followinginitiation of treatment with an active compound. An increase in averagesurvival time of a population may also be measured, for example, bycalculating for a population the average length of survival followingcompletion of a first round of treatment with an active compound.

Treating cancer may result in or can result in an increase in averagesurvival time of a population of treated subjects in comparison to apopulation of untreated subjects. Preferably, the average survival timewould be increased by more than 30 days; more preferably, by more than60 days; more preferably, by more than 90 days; and most preferably, bymore than 120 days. An increase in average survival time of a populationmay be measured by any reproducible means. An increase in averagesurvival time of a population may be measured, for example, bycalculating for a population the average length of survival followinginitiation of treatment with an active compound. An increase in averagesurvival time of a population may also be measured, for example, bycalculating for a population the average length of survival followingcompletion of a first round of treatment with an active compound.

Treating cancer may result in or can result in increase in averagesurvival time of a population of treated subjects in comparison to apopulation receiving monotherapy with a drug that is not a compound ofthe present invention, or a pharmaceutically acceptable salt, analog orderivative thereof. Preferably, the average survival time would beincreased by more than 30 days; more preferably, by more than 60 days;more preferably, by more than 90 days; and most preferably, by more than120 days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer may result in or can result in a decrease in themortality rate of a population of treated subjects in comparison to apopulation receiving carrier alone. Treating cancer may result in or canresult in a decrease in the mortality rate of a population of treatedsubjects in comparison to an untreated population. Treating cancer mayresult in or can result in a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the present invention,or a pharmaceutically acceptable salt, analog or derivative thereof.Preferably, the mortality rate would be decreased by more than 2%; morepreferably, by more than 5%; more preferably, by more than 10%; and mostpreferably, by more than 25%. A decrease in the mortality rate of apopulation of treated subjects may be measured by any reproduciblemeans. A decrease in the mortality rate of a population may be measured,for example, by calculating for a population the average number ofdisease-related deaths per unit time following initiation of treatmentwith an active compound. A decrease in the mortality rate of apopulation may also be measured, for example, by calculating for apopulation the average number of disease-related deaths per unit timefollowing completion of a first round of treatment with an activecompound.

Treating cancer may result in or can result in a decrease in tumorgrowth rate. Preferably, after treatment, tumor growth rate would bereduced by at least 5% relative to number prior to treatment; morepreferably, tumor growth rate would be reduced by at least 10%; morepreferably, reduced by at least 20%; more preferably, reduced by atleast 30%; more preferably, reduced by at least 40%; more preferably,reduced by at least 50%; even more preferably, reduced by at least 50%;and most preferably, reduced by at least 75%. Tumor growth rate may bemeasured by any reproducible means of measurement. Tumor growth rate canbe measured according to a change in tumor diameter per unit time.

Treating cancer may result in or can result in a decrease in tumorregrowth. Preferably, after treatment, tumor regrowth would be less than5%; more preferably, tumor regrowth would be less than 10%; morepreferably, less than 20%; more preferably, less than 30%; morepreferably, less than 40%; more preferably, less than 50%; even morepreferably, less than 50%; and most preferably, less than 75%. Tumorregrowth may be measured by any reproducible means of measurement. Tumorregrowth is measured, for example, by measuring an increase in thediameter of a tumor after a prior tumor shrinkage that followedtreatment. A decrease in tumor regrowth is indicated by failure oftumors to reoccur after treatment has stopped.

Treating or preventing a cell proliferative disorder may result in orcan result in a reduction in the rate of cellular proliferation.Preferably, after treatment, the rate of cellular proliferation would bereduced by at least 5%; more preferably, by at least 10%; morepreferably, by at least 20%; more preferably, by at least 30%; morepreferably, by at least 40%; more preferably, by at least 50%; even morepreferably, by at least 50%; and most preferably, by at least 75%. Therate of cellular proliferation may be measured by any reproducible meansof measurement. The rate of cellular proliferation is measured, forexample, by measuring the number of dividing cells in a tissue sampleper unit time.

Treating or preventing a cell proliferative disorder may result in orcan result in a reduction in the proportion of proliferating cells.Preferably, after treatment, the proportion of proliferating cells wouldbe reduced by at least 5%; more preferably, by at least 10%; morepreferably, by at least 20%; more preferably, by at least 30%; morepreferably, by at least 40%; more preferably, by at least 50%; even morepreferably, by at least 50%; and most preferably, by at least 75%. Theproportion of proliferating cells may be measured by any reproduciblemeans of measurement. Preferably, the proportion of proliferating cellsis measured, for example, by quantifying the number of dividing cellsrelative to the number of nondividing cells in a tissue sample. Theproportion of proliferating cells can be equivalent to the mitoticindex.

Treating or preventing a cell proliferative disorder may result in orcan result in a decrease in size of an area or zone of cellularproliferation. Preferably, after treatment, size of an area or zone ofcellular proliferation would be reduced by at least 5% relative to itssize prior to treatment; more preferably, reduced by at least 10%; morepreferably, reduced by at least 20%; more preferably, reduced by atleast 30%; more preferably, reduced by at least 40%; more preferably,reduced by at least 50%; even more preferably, reduced by at least 50%;and most preferably, reduced by at least 75%. Size of an area or zone ofcellular proliferation may be measured by any reproducible means ofmeasurement. The size of an area or zone of cellular proliferation maybe measured as a diameter or width of an area or zone of cellularproliferation.

Treating or preventing a cell proliferative disorder may result in orcan result in a decrease in the number or proportion of cells having anabnormal appearance or morphology. Preferably, after treatment, thenumber of cells having an abnormal morphology would be reduced by atleast 5% relative to its size prior to treatment; more preferably,reduced by at least 10%; more preferably, reduced by at least 20%; morepreferably, reduced by at least 30%; more preferably, reduced by atleast 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. An abnormal cellular appearance or morphology may be measuredby any reproducible means of measurement. An abnormal cellularmorphology can be measured by microscopy, e.g., using an inverted tissueculture microscope. An abnormal cellular morphology can take the form ofnuclear pleiomorphism.

As used herein, the term “selectively” means tending to occur at ahigher frequency in one population than in another population. Thecompared populations can be cell populations. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, polymorphor solvate thereof, acts selectively on a cancer or precancerous cellbut not on a normal cell. Preferably, a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, acts selectively to modulate one molecular target (e.g., atarget protein methyltransferase) but does not significantly modulateanother molecular target (e.g., a non-target protein methyltransferase).The invention also provides a method for selectively inhibiting theactivity of an enzyme, such as a protein methyltransferase. Preferably,an event occurs selectively in population A relative to population B ifit occurs greater than two times more frequently in population A ascompared to population B. An event occurs selectively if it occursgreater than five times more frequently in population A. An event occursselectively if it occurs greater than ten times more frequently inpopulation A; more preferably, greater than fifty times; even morepreferably, greater than 100 times; and most preferably, greater than1000 times more frequently in population A as compared to population B.For example, cell death would be said to occur selectively in cancercells if it occurred greater than twice as frequently in cancer cells ascompared to normal cells.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, can modulate the activity of amolecular target (e.g., a target protein methyltransferase). Modulatingrefers to stimulating or inhibiting an activity of a molecular target.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, modulates the activity ofa molecular target if it stimulates or inhibits the activity of themolecular target by at least 2-fold relative to the activity of themolecular target under the same conditions but lacking only the presenceof said compound. More preferably, a compound of the present invention,or a pharmaceutically acceptable salt, polymorph or solvate thereof,modulates the activity of a molecular target if it stimulates orinhibits the activity of the molecular target by at least 5-fold, atleast 10-fold, at least 20-fold, at least 50-fold, at least 100-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. The activityof a molecular target may be measured by any reproducible means. Theactivity of a molecular target may be measured in vitro or in vivo. Forexample, the activity of a molecular target may be measured in vitro byan enzymatic activity assay or a DNA binding assay, or the activity of amolecular target may be measured in vivo by assaying for expression of areporter gene.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, does not significantly modulate theactivity of a molecular target if the addition of the compound does notstimulate or inhibit the activity of the molecular target by greaterthan 10% relative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound.

As used herein, the term “isozyme selective” means preferentialinhibition or stimulation of a first isoform of an enzyme in comparisonto a second isoform of an enzyme (e.g., preferential inhibition orstimulation of a protein methyltransferase isozyme alpha in comparisonto a protein methyltransferase isozyme beta). Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, polymorphor solvate thereof, demonstrates a minimum of a fourfold differential,preferably a tenfold differential, more preferably a fifty folddifferential, in the dosage required to achieve a biological effect.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, demonstrates thisdifferential across the range of inhibition, and the differential isexemplified at the IC₅₀, i.e., a 50% inhibition, for a molecular targetof interest.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, to a cell or a subject inneed thereof can result in modulation (i.e., stimulation or inhibition)of an activity of a protein methyltransferase of interest.

The present invention provides methods to assess biological activity ofa compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof or methods of identifying a testcompound as an inhibitor of a mutant EZH2.

Point mutations of the EZH2 gene at a single amino acid residue (e.g.,Y641, A677, and A687) of EZH2 have been reported to be linked tolymphoma. More examples of EZH2 mutants and methods of treatment aredescribed in U.S. patent application Ser. No. 13/418,242, filed Mar. 12,2012, and published as US 2013-0040906, the entire content of which isincorporated herein by reference in its entirety.

In some assays, immunological reagents, e.g., antibodies and antigens,are employed. Fluorescence can be utilized in the measurement ofenzymatic activity in some assays. As used herein, “fluorescence” refersto a process through which a molecule emits a photon as a result ofabsorbing an incoming photon of higher energy by the same molecule.Specific methods for assessing the biological activity of the disclosedcompounds are described in the examples.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof; to a cell or a subject inneed thereof may or can result in modulation (i.e., stimulation orinhibition) of an activity of an intracellular target (e.g., substrate).Several intracellular targets may or can be modulated with the compoundsof the present invention, including, but not limited to, proteinmethyltransferase.

Activating refers to placing a composition of matter (e.g., protein ornucleic acid) in a state suitable for carrying out a desired biologicalfunction. A composition of matter capable of being activated also has anunactivated state. An activated composition of matter may have aninhibitory or stimulatory biological function, or both.

Elevation refers to an increase in a desired biological activity of acomposition of matter (e.g., a protein or a nucleic acid). Elevation mayoccur through an increase in concentration of a composition of matter.

As used herein, “a cell cycle checkpoint pathway” refers to abiochemical pathway that is involved in modulation of a cell cyclecheckpoint. A cell cycle checkpoint pathway may have stimulatory orinhibitory effects, or both, on one or more functions comprising a cellcycle checkpoint. A cell cycle checkpoint pathway is comprised of atleast two compositions of matter, preferably proteins, both of whichcontribute to modulation of a cell cycle checkpoint. A cell cyclecheckpoint pathway may be activated through an activation of one or moremembers of the cell cycle checkpoint pathway. Preferably, a cell cyclecheckpoint pathway is a biochemical signaling pathway.

As used herein, “cell cycle checkpoint regulator” refers to acomposition of matter that can function, at least in part, in modulationof a cell cycle checkpoint. A cell cycle checkpoint regulator may havestimulatory or inhibitory effects, or both, on one or more functionscomprising a cell cycle checkpoint. A cell cycle checkpoint regulatorcan be a protein or not a protein.

Treating cancer or a cell proliferative disorder may result in or canresult in cell death, and preferably, cell death would result in adecrease of at least 10% in number of cells in a population. Morepreferably, cell death means a decrease of at least 20%; morepreferably, a decrease of at least 30%; more preferably, a decrease ofat least 40%; more preferably, a decrease of at least 50%; mostpreferably, a decrease of at least 75%. Number of cells in a populationmay be measured by any reproducible means. A number of cells in apopulation can be measured by fluorescence activated cell sorting(FACS), immunofluorescence microscopy and light microscopy. Methods ofmeasuring cell death are as shown in Li et al., Proc Natl Acad Sci USA.100(5): 2674-8, 2003. In an aspect, cell death occurs by apoptosis.

Preferably, an effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, polymorph or solvate thereof,would not be significantly cytotoxic to normal cells. A therapeuticallyeffective amount of a compound is not significantly cytotoxic to normalcells if administration of the compound in a therapeutically effectiveamount does not induce cell death in greater than 10% of normal cells. Atherapeutically effective amount of a compound does not significantlyaffect the viability of normal cells if administration of the compoundin a therapeutically effective amount does not induce cell death ingreater than 10% of normal cells. In an aspect, cell death occurs byapoptosis.

Contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, may orcan induce or activate cell death selectively in cancer cells.Administering to a subject in need thereof a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, may or can induce or activate cell death selectively in cancercells. Contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, may orcan induce cell death selectively in one or more cells affected by acell proliferative disorder. Preferably, administering to a subject inneed thereof a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, would induce cell deathselectively in one or more cells affected by a cell proliferativedisorder.

One aspect of the present invention relates to a method of treating orpreventing cancer (e.g., the course of which can be influenced bymodulating EZH2-mediated protein methylation) by administering acompound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, to a subject in need thereof, whereadministration of the compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, resultsin one or more of the following: prevention of cancer cell proliferationby accumulation of cells in one or more phases of the cell cycle (e.g.G1, G1/S, G2/M), or induction of cell senescence, or promotion of tumorcell differentiation; promotion of cell death in cancer cells viacytotoxicity, necrosis or apoptosis, without a significant amount ofcell death in normal cells, antitumor activity in animals with atherapeutic index of at least 2. As used herein, “therapeutic index” isthe maximum tolerated dose divided by the efficacious dose. The presentinvention also relates to a method used to identify suitable candidatesfor treating or preventing cancer.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3^(rd) edition), Cold SpringHarbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., CurrentProtocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., CurrentProtocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., ThePharmacological Basis of Therapeutics (1975), Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 18^(th) edition (1990).These texts can, of course, also be referred to in making or using anaspect of the invention.

As used herein, “combination therapy” or “co-therapy” includes theadministration of a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, and atleast a second agent as part of a specific treatment regimen intended toprovide the beneficial effect from the co-action of these therapeuticagents. The beneficial effect of the combination includes, but is notlimited to, pharmacokinetic or pharmacodynamic co-action resulting fromthe combination of therapeutic agents. Administration of thesetherapeutic agents in combination typically is carried out over adefined time period (usually minutes, hours, days or weeks dependingupon the combination selected). “Combination therapy” may be, butgenerally is not, intended to encompass the administration of two ormore of these therapeutic agents as part of separate monotherapyregimens that incidentally and arbitrarily result in the combinations ofthe present invention.

“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, wherein each therapeuticagent is administered at a different time, as well as administration ofthese therapeutic agents, or at least two of the therapeutic agents, ina substantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected may be administered by intravenous injection while the othertherapeutic agents of the combination may be administered orally.Alternatively, for example, all therapeutic agents may be administeredorally or all therapeutic agents may be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical.

“Combination therapy” also embraces the administration of thetherapeutic agents as described above in further combination with otherbiologically active ingredients and non-drug therapies (e.g., surgery orradiation treatment). Where the combination therapy further comprises anon-drug treatment, the non-drug treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and non-drug treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

A compound of the present invention, or a pharmaceutically acceptablesalt, analog or derivative thereof, may be administered in combinationwith a second chemotherapeutic agent. The second chemotherapeutic agent(also referred to as an anti-neoplastic agent or anti-proliferativeagent) can be an alkylating agent; an antibiotic; an anti-metabolite; adetoxifying agent; an interferon; a polyclonal or monoclonal antibody;an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; ahormone; a mitotic inhibitor; an MTOR inhibitor; a multi-kinaseinhibitor; a serine/threonine kinase inhibitor; a tyrosine kinaseinhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, anaromatase inhibitor, an anthracycline, a microtubule targeting drug, atopoisomerase poison drug, an inhibitor of a molecular target or enzyme(e.g., a kinase or a protein methyltransferase), a cytidine analoguedrug or any chemotherapeutic, anti-neoplastic or anti-proliferativeagent listed in www.cancer.org/docroot/cdg/cdg_(—)0.asp.

Exemplary alkylating agents include, but are not limited to,cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan(Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU);dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel);ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran);carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide(Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin(Zanosar).

Exemplary antibiotics include, but are not limited to, doxorubicin(Adriamycin); doxorubicin liposomal (Doxil); mitoxantrone (Novantrone);bleomycin (Blenoxane); daunorubicin (Cerubidine); daunorubicin liposomal(DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin(Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin(Nipent); or valrubicin (Valstar).

Exemplary anti-metabolites include, but are not limited to, fluorouracil(Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine(Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine(Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar);cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal(DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine(FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine(Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall);thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

Exemplary detoxifying agents include, but are not limited to, amifostine(Ethyol) or mesna (Mesnex).

Exemplary interferons include, but are not limited to, interferonalfa-2b (Intron A) or interferon alfa-2a (Roferon-A).

Exemplary polyclonal or monoclonal antibodies include, but are notlimited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab(Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab(Vectibix); tositumomab/iodine131 tositumomab (Bexxar); alemtuzumab(Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab(Mylotarg); eculizumab (Soliris) ordenosumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib(Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva);panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab(Emd7200) or EKB-569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab(Herceptin); lapatinib (Tykerb) or AC-480.

Histone Deacetylase Inhibitors include, but are not limited to,vorinostat (Zolinza).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox;Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron;Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole(Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane(Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole(Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone(Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin);toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron);abarelix (Plenaxis); or testolactone (Teslac).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel(Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin;Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos;VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole;epothilone; vinorelbine (Navelbine); camptothecin (CPT); irinotecan(Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

Exemplary MTOR inhibitors include, but are not limited to, everolimus(Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; orAP23573.

Exemplary multi-kinase inhibitors include, but are not limited to,sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474;PKC-412; motesanib; or AP24534.

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol;seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412;bryostatin; KAI-9803; SF1126; VX-680; Azd1152; Arry-142886 (AZD-6244);SC10-469; GW681323; CC-401; CEP-1347 or PD 332991.

Exemplary tyrosine kinase inhibitors include, but are not limited to,erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib(Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab(Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux);panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath);gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient);dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584);CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

Exemplary VEGF/VEGFR inhibitors include, but are not limited to,bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent);ranibizumab; pegaptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to,paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilonesand navelbine.

Exemplary topoisomerase poison drugs include, but are not limited to,teniposide, etoposide, adriamycin, camptothecin, daunorubicin,dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.

Exemplary taxanes or taxane derivatives include, but are not limited to,paclitaxel and docetaxol.

Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferativeagents include, but are not limited to, altretamine (Hexalen);isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin(Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase(Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine(Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak);porfimer (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid);bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel);arsenic trioxide (Trisenox); verteporfin (Visudyne); mimosine(Leucenol); (1M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 Mpotassium oxonate) or lovastatin.

In another aspect, the second chemotherapeutic agent can be a cytokinesuch as G-CSF (granulocyte colony stimulating factor). In anotheraspect, a compound of the present invention, or a pharmaceuticallyacceptable salt, analog or derivative thereof, may be administered incombination with radiation therapy. Radiation therapy can also beadministered in combination with a compound of the present invention andanother chemotherapeutic agent described herein as part of a multipleagent therapy. In yet another aspect, a compound of the presentinvention, or a pharmaceutically acceptable salt, analog or derivativethereof, may be administered in combination with standard chemotherapycombinations such as, but not restricted to, CMF (cyclophosphamide,methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC(5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC(adriamycin, cyclophosphamide, and paclitaxel), rituximab, Xeloda(capecitabine), Cisplatin (CDDP), Carboplatin, TS-1 (tegafur, gimestatand otastat potassium at a molar ratio of 1:0.4:1), Camptothecin-11(CPT-11, Irinotecan or Camptosar™), CHOP (cyclophosphamide,hydroxydaunorubicin, oncovin, and prednisone or prednisolone), R-CHOP(rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisoneor prednisolone), or CMFP (cyclophosphamide, methotrexate,5-fluorouracil and prednisone).

In preferred embodiments, a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, may beadministered with an inhibitor of an enzyme, such as a receptor ornon-receptor kinase. Receptor and non-receptor kinases are, for example,tyrosine kinases or serine/threonine kinases. Kinase inhibitorsdescribed herein are small molecules, polynucleic acids, polypeptides,or antibodies.

Exemplary kinase inhibitors include, but are not limited to, Bevacizumab(targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab/Erbitux(targets Erb1), Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targetsErb2), Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF),Pegaptanib (targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib(targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2),GW-572016/lapatinib ditosylate (targets HER2/Erb2), Panitumumab/Vectibix(targets EGFR), Vandetinib (targets RET/VEGFR), E7080 (multiple targetsincluding RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166(targets EGFR), Canertinib/CI-1033 (targets EGFR),Sunitinib/SU-11464/Sutent (targets EGFR and FLT3), Matuzumab/Emd7200(targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR),PKC-412 (targets VEGR and FLT3), Vatalanib/Ptk787/ZK222584 (targetsVEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), MLN518 (targetsFLT3), XL999 (targets FLT3), VX-322 (targets FLT3), Azd0530 (targetsSRC), BMS-354825 (targets SRC), SKI-606 (targets SRC), CP-690 (targetsJAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 (targetsJAK), sorafenib/Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3,PDGFR-β, KIT, FLT-3, and RET), Dasatinib/Sprycel (BCR/ABL and Src),AC-220 (targets Flt3), AC-480 (targets all HER proteins, “panHER”),Motesanib diphosphate (targets VEGF1-3, PDGFR, and c-kit), Denosumab(targets RANKL, inhibits SRC), AMG888 (targets HER3), and AP24534(multiple targets including Flt3).

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR),Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1),Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK),Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032(targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC),Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K),VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase),Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK),GW681323 (targets MAP/MEK), CC-401 (targets JNK), CEP-1347 (targetsJNK), and PD 332991 (targets CDK).

The disorder in which EZH2-mediated protein methylation plays a part canbe a neurological disease. The compounds of this invention may thus alsobe used for treating or studying neurologic diseases such as epilepsy,schizophrenia, bipolar disorder or other psychological and/orpsychiatric disorders, neuropathies, skeletal muscle atrophy, andneurodegenerative diseases, e.g., a neurodegenerative disease. Exemplaryneurodegenerative diseases include: Alzheimer's, Amyotrophic LateralSclerosis (ALS), and Parkinson's disease. Another class ofneurodegenerative diseases includes diseases caused at least in part byaggregation of poly-glutamine. Diseases of this class include:Huntington's Diseases, Spinalbulbar Muscular Atrophy (SBMA or Kennedy'sDisease) Dentatorubropallidoluysian Atrophy (DRPLA), SpinocerebellarAtaxia 1 (SCA1), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease(MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7(SCA7), and Spinocerebellar Ataxia 12 (SCA12).

Any other disease in which epigenetic methylation, which is mediated byEZH2, plays a role may be treatable or preventable using compounds andmethods described herein, or such diseases and potential treatmentsthereof may be studied with the compounds described herein.

The present invention also provides pharmaceutical compositionscomprising a compound of any of the Formulae described herein incombination with at least one pharmaceutically acceptable excipient orcarrier.

A “pharmaceutical composition” is a formulation containing the compoundsof the present invention in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, inhalational, buccal, sublingual, intrapleural,intrathecal, intranasal, and the like. Dosage forms for the topical ortransdermal administration of a compound of this invention includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In one embodiment, the active compound is mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, anions, cations, materials, compositions, carriers, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the invention can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the invention may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not so high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In a preferred aspect,the disease or condition to be treated is cancer. In another aspect, thedisease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent invention may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol and sorbitol, and sodium chloridein the composition. Prolonged absorption of the injectable compositionscan be brought about by including in the composition an agent whichdelays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the invention vary depending on theagent, the age, weight, and clinical condition of the recipient patient,and the experience and judgment of the clinician or practitioneradministering the therapy, among other factors affecting the selecteddosage. Generally, the dose should be sufficient to result in slowing,and preferably regressing, the growth of the tumors and also preferablycausing complete regression of the cancer. Dosages can range from about0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects,dosages can range from about 1 mg/kg per day to about 1000 mg/kg perday. In an aspect, the dose will be in the range of about 0.1 mg/day toabout 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day toabout 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about1 g/day, in single, divided, or continuous doses (which dose may beadjusted for the patient's weight in kg, body surface area in m², andage in years). An effective amount of a pharmaceutical agent is thatwhich provides an objectively identifiable improvement as noted by theclinician or other qualified observer. For example, regression of atumor in a patient may be measured with reference to the diameter of atumor. Decrease in the diameter of a tumor indicates regression.Regression is also indicated by failure of tumors to reoccur aftertreatment has stopped. As used herein, the term “dosage effectivemanner” refers to amount of an active compound to produce the desiredbiological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The compounds of the present invention are capable of further formingsalts. All of these forms are also contemplated within the scope of theclaimed invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compounds of the present invention wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present invention also encompassessalts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. In the salt form, it is understood thatthe ratio of the compound to the cation or anion of the salt can be 1:1,or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compounds of the present invention can also be prepared as esters,for example, pharmaceutically acceptable esters. For example, acarboxylic acid function group in a compound can be converted to itscorresponding ester, e.g., a methyl, ethyl or other ester. Also, analcohol group in a compound can be converted to its corresponding ester,e.g., acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperitoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound is administeredorally. One skilled in the art will recognize the advantages of certainroutes of administration.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counter,or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the invention can be found in Remington: the Science and Practice ofPharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995). Inan embodiment, the compounds described herein, and the pharmaceuticallyacceptable salts thereof, are used in pharmaceutical preparations incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present invention areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentinvention. The examples do not limit the claimed invention. Based on thepresent disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present invention.

In the synthetic schemes described herein, compounds may be drawn withone particular configuration for simplicity. Such particularconfigurations are not to be construed as limiting the invention to oneor another isomer, tautomer, regioisomer or stereoisomer, nor does itexclude mixtures of isomers, tautomers, regioisomers or stereoisomers;however, it will be understood that a given isomer, tautomer,regioisomer or stereoisomer may have a higher level of activity thananother isomer, tautomer, regioisomer or stereoisomer.

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, using techniques known in theart. General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

All publications and patent documents cited herein are incorporatedherein by reference as if each such publication or document wasspecifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any is pertinent prior art, nor does it constituteany admission as to the contents or date of the same. The inventionhaving now been described by way of written description, those of skillin the art will recognize that the invention can be practiced in avariety of embodiments and that the foregoing description and examplesbelow are for purposes of illustration and not limitation of the claimsthat follow.

PREPARATORY EXAMPLE 1 General PyBOP Coupling Protocol

The carboxylic acid (1 equiv.) was then dissolved in DMSO and anappropriate methanamine (2 eq.) was added to it. The reaction mixturewas stirred at room temperature for 15 min before PYBOP (1.5 equiv.) andtriethyl amine (1 equiv.) was added to it and stirring was continued forovernight. After completion of the reaction, reaction mass was pouredinto ice, extracted with 10% MeOH/DCM. Combined organic layers weredried, concentrated to obtain crude; which then purified by columnchromatography prep. HPLC to afford the target compound.

EXAMPLE 1 (2,4-dimethyl-2H-indazol-7-yl)methanamine Step 1: Synthesis of7-bromo-2,4-dimethyl-2H-indazole

To a solution of 7-bromo-4-methyl-1H-indazole (1 equiv.) inacetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added andreaction was heated at 80 oC for 1.5 h. On completion, it was cooled andquenched by addition of water. Extraction was carried out using ethylacetate. Organic layer was dried over Na2SO4 and crude compound wascolumn purified to afford the title compound. (Polar isomer confirmed asN-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOEexperimentation).

Step 2: Synthesis of 2,4-dimethyl-2H-indazole-7-carbonitrile

To a solution of 7-bromo-2,4-dimethyl-2H-indazole (1 eq.) in NMP, wasadded CuCN (2 equiv.) and heated at 130 oC for 16 h. On completion,water was added to quench the reaction, solid precipitated was filteredand purified by column chromatography to afford the title compound(40-60% yield)

Step 3: Synthesis of (2,4-dimethyl-2H-indazol-7-yl)methanamine

To a solution of 2,4-dimethyl-2H-indazole-7-carbonitrile (1 equiv.) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford the title compound (quant.yield).

EXAMPLE 2 (5,7-dimethylimidazo[1,2-a]pyridin-8-yl)methanamine Step 1:Synthesis of 5,7-dimethylimidazo[1,2-a]pyridine-8-carbonitrile

To a stirred solution of compound 2-amino-4,6-dimethylnicotinonitrile (1equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2equiv.) and reaction was heated at 80 oC for 16 h. On completion, it wasquenched by 1N NaOH till pH 8. Solid precipitated was filtered andvacuum dried to afford the title compound (75% yield).

Step 2: Synthesis of (5,7-dimethylimidazo[1,2-a]pyridin-8-yl)methanamine

To a solution of 5,7-dimethylimidazo[1,2-a]pyridine-8-carbonitrile (1equiv.) in methanol and aq. ammonia solution (9:1), a catalytic amountof Raney Nickel was added. The reaction mass was stirred at roomtemperature under hydrogen pressure (balloon pressure) for 2-5 h. Oncompletion of reaction, it was filtered through a celite bed and thefiltrate was concentrated under reduce pressure to afford respectiveamines (quantitative yield).

EXAMPLE 3 (7-methylimidazo[1,2-a]pyridin-8-yl)methanamine Step 1:Synthesis of 7-methylimidazo[1,2-a]pyridine-8-carbonitrile

To a stirred solution of compound 2-amino-4-methylnicotinonitrile (1equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2equiv.) and the reaction was heated at 80 oC for 16 h. On completion, itwas quenched by 1N NaOH till pH 8. Solid precipitated was filtered andvacuum dried to afford the title compound (75% yield).

Step 2: Synthesis of (7-methylimidazo[1,2-a]pyridin-8-yl)methanamine

To a solution of 7-methylimidazo[1,2-a]pyridine-8-carbonitrile (1 eq) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford respective amines(quantitative yield).

EXAMPLE 4 Imidazo[1,2-a]pyridin-8-ylmethanamine

To a solution of imidazo[1,2-a]pyridine-8-carbonitrile (1 equiv.) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford respective amines(quantitative yield).

EXAMPLE 5 (2,6-dimethyl-2H-indazol-7-yl)methanamine Step 1: Synthesis of7-bromo-2,6-dimethyl-2H-indazole

To a solution of 7-bromo-6-methyl-1H-indazole (1 equiv.) inacetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 eq.) was added and reactionwas heated at 80 oC for 1.5 h. On completion, it was cooled and quenchedby addition of water. Extraction was carried out using ethyl acetate.Organic layer was dried over Na2SO4 and crude compound was columnpurified to afford the title compound. (Polar isomer confirmed asN-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOEexperimentation).

Step 2: Synthesis of 2,6-dimethyl-2H-indazole-7-carbonitrile

To a solution of 7-bromo-2,6-dimethyl-2H-indazole (1 equiv.) in NMP, wasadded CuCN (2 equiv.) and heated at 130 oC for 16 h. On completion,water was added to quench the reaction, solid precipitated was filteredand purified by column chromatography to afford the title compound(40-60% yield)

Step 3: Synthesis of (2,6-dimethyl-2H-indazol-7-yl)methanamine

To a solution of 2,6-dimethyl-2H-indazole-7-carbonitrile (1 equiv.) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford the title compound (quant.yield).

EXAMPLE 6 (2-methyl-2H-indazol-7-yl)methanamine Step 1: Synthesis of2-methyl-2H-indazole-7-carbonitrile

To a solution of 1H-indazole-7-carbonitrile (1 equiv.) in acetonitrile,Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heatedat 80 oC for 1.5 h. On completion, it was cooled and quenched byaddition of water. Extraction was carried out using ethyl acetate.Organic layer was dried over Na2SO4 and crude compound was columnpurified to afford the title compound. (Polar isomer confirmed asN-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOEexperimentation).

Step 2: Synthesis of (2-methyl-2H-indazol-7-yl)methanamine

To a solution of 2-methyl-2H-indazole-7-carbonitrile (1 equiv.) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford the title compound (quant.yield).

EXAMPLE 7 pyrazolo[1,5-a]pyridin-7-ylmethanamine

To a solution of pyrazolo[1,5-a]pyridine-7-carbonitrile (1 equiv.) inmethanol and aq. ammonia solution (9:1), catalytic amount of RaneyNickel was added. Reaction mass was stirred at room temperature underhydrogen pressure (balloon pressure) for 2-5 h. On completion ofreaction, it was filtered through celite bed and filtrate wasconcentrated under reduce pressure to afford the title compound (quant.yield).

EXAMPLE 8 Bioassay Protocol and General Methods

Protocol for Wild-Type and Mutant PRC2 Enzyme Assays

General Materials.

S-adenosylmethionine (SAM), S-adenosylhomocyteine (SAH), bicine, KCl,Tween20, dimethylsulfoxide (DMSO) and bovine skin gelatin (BSG) can bepurchased from Sigma-Aldrich at the highest level of purity possible.Dithiothreitol (DTT) was purchased from EMD. ³H-SAM can be purchasedfrom American Radiolabeled Chemicals with a specific activity of 80Ci/mmol. 384-well streptavidin Flashplates can be purchased fromPerkinElmer.

Substrates.

Peptides representative of human histone H3 residues 21-44 containingeither an unmodified lysine 27 (H3K27me0) or dimethylated lysine 27(H3K27me2) are synthesized with a C-terminal G(K-biotin) linker-affinitytag motif and a C-terminal amide cap by 21^(st) Century Biochemicals.The peptides are high-performance liquid chromatography (HPLC) purifiedto greater than 95% purity and confirmed by liquid chromatography massspectrometry (LC-MS). The sequences are listed below.

H3K27me0: (SEQ ID NO: 1) ATKAARKSAPATGGVKKPHRYRPGGK(biotin)-amideH3K27me2: (SEQ ID NO: 2) ATKAARK(me2)SAPATGGVKKPHRYRPGGK(biotin)-amide

Chicken erythrocyte oligonucleosomes are purified from chicken bloodaccording to established procedures.

Recombinant PRC2 Enzymes.

Human PRC2 enzymes are purified as 4-component enzyme complexesco-expressed in Spodoptera frugiperda (sf9) cells using a baculovirusexpression system. The subunits expressed are wild-type EZH2(NM_(—)004456) or EZH2 Y641F, N, H, S or C mutants generated from thewild-type EZH2 construct, EED (NM_(—)003797), Suz12 (NM_(—)015355) andRbAp48 (NM_(—)005610). The EED subunit contains an N-terminal FLAG tagthat is used to purify the entire 4-component complex from 49 celllysates. The purity of the complexes meets or exceeds 95% as determinedby SDS-PAGE and Agilent Bioanalyzer analysis. Concentrations of enzymestock concentrations (generally 0.3-1.0 mg/mL) is determined using aBradford assay against a bovine serum albumin (BSA) standard.

General Procedure for PRC2 Enzyme Assays on Peptide Substrates.

The assays are all performed in a buffer consisting of 20 mM bicine(pH=7.6), 0.5 mM DTT, 0.005% BSG and 0.002% Tween20, prepared on the dayof use. Compounds in 100% DMSO (1 μL) are spotted into polypropylene384-well V-bottom plates (Greiner) using a Platemate 2×3 outfitted witha 384-channel pipet head (Thermo). DMSO (1 μL) is added to columns 11,12, 23, 24, rows A H for the maximum signal control, and SAH, a knownproduct and inhibitor of PRC2 (1 pt) is added to columns 11, 12, 23, 24,rows I-P for the minimum signal control. A cocktail (40 pt) containingthe wild-type PRC2 enzyme and H3K27me0 peptide or any of the Y641 mutantenzymes and H3K27me2 peptide is added by Multidrop Combi (Thermo). Thecompounds are allowed to incubate with PRC2 for 30 min at 25° C., then acocktail (10 pt) containing a mixture of non-radioactive and ³H-SAM isadded to initiate the reaction (final volume=51 pt). In all cases, thefinal concentrations are as follows: wild-type or mutant PRC2 enzyme was4 nM, SAH in the minimum signal control wells was 1 mM and the DMSOconcentration was 1%. The final concentrations of the rest of thecomponents are indicated in Table 4, below. The assays are stopped bythe addition of non-radioactive SAM (10 μL) to a final concentration of600 μM, which dilutes the ³H-SAM to a level where its incorporation intothe peptide substrate is no longer detectable. 50 μL of the reaction inthe 384-well polypropylene plate is then transferred to a 384-wellFlashplate and the biotinylated peptides are allowed to bind to thestreptavidin surface for at least 1 h before being washed three timeswith 0.1% Tween20 in a Biotek EL×405 plate washer. The plates are thenread in a PerkinElmer TopCount platereader to measure the quantity of³H-labeled peptide bound to the Flashplate surface, measured asdisintegrations per minute (dpm) or alternatively, referred to as countsper minute (cpm).

TABLE 4 Final concentrations of components for each assay variationbased upon EZH2 identity (wild-type or Y641 mutant EZH2) PRC2 Enzyme(denoted Peptide Non-radioactive ³H-SAM by EZH2 identity) (nM) SAM (nM)(nM) Wild-type 185 1800 150 Y641F 200 850 150 Y641N 200 850 150 Y641H200 1750 250 Y641S 200 1300 200 Y641C 200 3750 250

General Procedure for Wild-Type PRC2 Enzyme Assay on OligonucleosomeSubstrate.

The assays are performed in a buffer consisting of 20 mM bicine(pH=7.6), 0.5 mM DTT, 0.005% BSG, 100 mM KCl and 0.002% Tween20,prepared on the day of use. Compounds in 100% DMSO (1 μL) were spottedinto polypropylene 384-well V-bottom plates (Greiner) using a Platemate2×3 outfitted with a 384-channel pipet head (Thermo). DMSO (1 μL) isadded to columns 11, 12, 23, 24, rows A H for the maximum signalcontrol, and SAH, a known product and inhibitor of PRC2 (1 μL) was addedto columns 11, 12, 23, 24, rows I P for the minimum signal control. Acocktail (40 μL) containing the wild-type PRC2 enzyme and chickenerythrocyte oligonucleosome is added by Multidrop Combi (Thermo). Thecompounds are allowed to incubate with PRC2 for 30 min at 25° C., then acocktail (10 μL) containing a mixture of non-radioactive and ³H-SAM isadded to initiate the reaction (final volume=51 μL). The finalconcentrations are as follows: wild-type PRC2 enzyme is 4 nM,non-radioactive SAM is 430 nM, ³H-SAM was 120 nM, chicken erythrocyteolignonucleosome was 120 nM, SAH in the minimum signal control wells is1 mM and the DMSO concentration was 1%. The assay is stopped by theaddition of non-radioactive SAM (10 μL) to a final concentration of 600μM, which dilutes the ³H-SAM to a level where its incorporation into thechicken erythrocyte olignonucleosome substrate is no longer detectable.50 μL of the reaction in the 384-well polypropylene plate is thentransferred to a 384-well Flashplate and the chicken erythrocytenucleosomes were immobilized to the surface of the plate, which is thenwashed three times with 0.1% Tween20 in a Biotek EL×405 plate washer.The plates are then read in a PerkinElmer TopCount platereader tomeasure the quantity of ³H-labeled chicken erythrocyte oligonucleosomebound to the Flashplate surface, measured as disintegrations per minute(dpm) or alternatively, referred to as counts per minute (cpm).

% Inhibition Calculation

${\%\mspace{14mu}{inh}} = {100 - {( \frac{{dpm}_{cmpd} - {dpm}_{\min}}{{dpm}_{\max} - {dpm}_{\min}} ) \times 100}}$

Where dpm=disintegrations per minute, cmpd=signal in assay well, and minand max are the respective minimum and maximum signal controls.

Four-Parameter IC₅₀ Fit

$Y = {{Bottom} + \frac{( {{Top} - {Bottom}} )}{1 + ( \frac{X}{{IC}_{50}} )^{{Hill}\mspace{11mu}{Coefficient}}}}$

Where top and bottom are the normally allowed to float, but may be fixedat 100 or 0 respectively in a 3-parameter fit. The Hill Coefficientnormally allowed to float but may also be fixed at 1 in a 3-parameterfit. Y is the % inhibition and X is the compound concentration.

WSU-DLCL2 Methylation Assay

WSU-DLCL2 suspension cells are purchased from DSMZ (German Collection ofMicroorganisms and Cell Cultures, Braunschweig, Germany). RPMI/GlutamaxMedium, Penicillin-Streptomycin, Heat Inactivated Fetal Bovine Serum,and D-PBS were purchased from Life Technologies, Grand Island, N.Y.,USA. Extraction Buffer and Neutralization Buffer (5×) were purchasedfrom Active Motif, Carlsbad, Calif., USA. Rabbit anti-Histone H3antibody is purchased from Abcam, Cambridge, Mass., USA. Rabbitanti-H3K27me3 and HRP-conjugated anti-rabbit-IgG are purchased from CellSignaling Technology, Danvers, Mass., USA. TMB “Super Sensitive”substrate is sourced from BioFX Laboratories, Owings Mills, Md., USA.IgG-free Bovine Serum Albumin is purchased from Jackson ImmunoResearch,West Grove, Pa., USA. PBS with Tween (10×PBST) was purchased from KPL,Gaithersburg, Md., USA. Sulfuric Acid is purchased from Ricca Chemical,Arlington, Tex., USA. Immulon ELISA plates were purchased from Thermo,Rochester, N.Y., USA. V-bottom cell culture plates are purchased fromCorning Inc., Corning, N.Y., USA. V-bottom polypropylene plates werepurchased from Greiner Bio-One, Monroe, N.C., USA.

WSU-DLCL2 suspension cells are maintained in growth medium (RPMI 1640supplemented with 10% v/v heat inactivated fetal bovine serum and 100units/mL penicillin-streptomycin) and cultured at 37° C. under 5% CO₂.Under assay conditions, cells are incubated in Assay Medium (RPMI 1640supplemented with 20% v/v heat inactivated fetal bovine serum and 100units/mL penicillin-streptomycin) at 37° C. under 5% CO₂ on a plateshaker.

WSU-DLCL2 cells are seeded in assay medium at a concentration of 50,000cells per mL to a 96-well V-bottom cell culture plate with 200 μL perwell. Compound (1 μL) from 96 well source plates is added directly toV-bottom cell plate. Plates are incubated on a titer-plate shaker at 37°C., 5% CO₂ for 96 hours. After four days of incubation, plates are spunat 241×g for five minutes and medium was aspirated gently from each wellof cell plate without disturbing cell pellet. Pellet is resuspended in200 μL DPBS and plates are spun again at 241×g for five minutes. Thesupernatant is aspirated and cold (4° C.) Extraction buffer (100 μL) isadded per well. Plates are incubated at 4° C. on orbital shaker for twohours. Plates are spun at 3427×g×10 minutes. Supernatant (80 μL perwell) is transferred to its respective well in 96 well V-bottompolypropylene plate. Neutralization Buffer 5× (20 μL per well) is addedto V-bottom polypropylene plate containing supernatant. V-bottompolypropylene plates containing crude histone preparation (CHP) areincubated on orbital shaker x five minutes. Crude Histone Preparationsare added (2 μL per well) to each respective well into duplicate 96 wellELISA plates containing 100 μL Coating Buffer (1×PBS+BSA 0.05% w/v).Plates are sealed and incubated overnight at 4° C. The following day,plates were washed three times with 300 μL per well 1×PBST. Wells areblocked for two hours with 300 μL per well ELISA Diluent ((PBS (1×) BSA(2% w/v) and Tween20 (0.05% v/v)). Plates are washed three times with1×PBST. For the Histone H3 detection plate, 100 μL per well are added ofanti-Histone-H3 antibody (Abcam, ab1791) diluted 1:10,000 in ELISADiluent. For H3K27 trimethylation detection plate, 100 μL per well areadded of anti-H3K27me3 diluted 1:2000 in ELISA diluent. Plates areincubated for 90 minutes at room temperature. Plates are washed threetimes with 300 μL 1×PBST per well. For Histone H3 detection, 100 μL ofHRP-conjugated anti-rabbit IgG antibody diluted to 1:6000 in ELISAdiluent is added per well. For H3K27me3 detection, 100 μL of HRPconjugated anti-rabbit IgG antibody diluted to 1:4000 in ELISA diluentis added per well. Plates are incubated at room temperature for 90minutes. Plates are washed four times with 1×PBST 300 μL per well. TMBsubstrate 100 μL is added per well. Histone H3 plates are incubated forfive minutes at room temperature. H3K27me3 plates were incubated for 10minutes at room temperature. The reaction is stopped with sulfuric acid1N (100 μL per well). Absorbance for each plate was read at 450 nm.

First, the ratio for each well is determined by:

$( \frac{H\; 3\mspace{11mu} K\; 27\mspace{14mu}{ms}\; 3\mspace{11mu}{OD}\; 450\mspace{20mu}{value}}{{Histone}\mspace{14mu} H\; 3\mspace{14mu}{OD}\; 450\mspace{14mu}{value}} )$

Each plate includes eight control wells of DMSO only treatment (MinimumInhibition) as well as eight control wells for maximum inhibition(Background wells).

The average of the ratio values for each control type is calculated andused to determine the percent inhibition for each test well in theplate. Test compound is serially diluted three-fold in DMSO for a totalof ten test concentrations, beginning at 25 μM. Percent inhibition isdetermined and IC₅₀ curves were generated using duplicate wells perconcentration of compound.

${{Percent}\mspace{14mu}{Inhibition}} = {100 - ( {( \frac{\begin{matrix}{( {{Individual}\mspace{14mu}{Test}\mspace{14mu}{Sample}\mspace{14mu}{Ratio}} ) -} \\( {{Background}\mspace{14mu}{Avg}\mspace{14mu}{Ratio}} )\end{matrix}}{\begin{matrix}{( {{Minimum}\mspace{14mu}{Inhibition}\mspace{14mu}{Ratio}} ) -} \\( {{Background}\mspace{14mu}{Average}\mspace{14mu}{Ratio}} )\end{matrix}} )*100} )}$Cell Proliferation Analysis

WSU-DLCL2 suspension cells are purchased from DSMZ (German Collection ofMicroorganisms and Cell Cultures, Braunschweig, Germany). RPMI/GlutamaxMedium, Penicillin-Streptomycin, Heat Inactivated Fetal Bovine Serum arepurchased from Life Technologies, Grand Island, N.Y., USA. V-bottompolypropylene 384-well plates are purchased from Greiner Bio-One,Monroe, N.C., USA. Cell culture 384-well white opaque plates arepurchased from Perkin Elmer, Waltham, Mass., USA. Cell-Titer Glo® ispurchased from Promega Corporation, Madison, Wis., USA. SpectraMax M5plate reader is purchased from Molecular Devices LLC, Sunnyvale, Calif.,USA.

WSU-DLCL2 suspension cells are maintained in growth medium (RPMI 1640supplemented with 10% v/v heat inactivated fetal bovine serum andcultured at 37° C. under 5% CO₂. Under assay conditions, cells areincubated in Assay Medium (RPMI 1640 supplemented with 20% v/v heatinactivated fetal bovine serum and 100 units/mL penicillin-streptomycin)at 37° C. under 5% CO₂.

For the assessment of the effect of compounds on the proliferation ofthe WSU-DLCL2 cell line, exponentially growing cells are plated in384-well white opaque plates at a density of 1250 cell/ml in a finalvolume of 50 μl of assay medium. A compound source plate is prepared byperforming triplicate nine-point 3-fold serial dilutions in DMSO,beginning at 10 mM (final top concentration of compound in the assay was20 μM and the DMSO was 0.2%). A 100 nL aliquot from the compound stockplate is added to its respective well in the cell plate. The 100%inhibition control consists of cells treated with 200 nM finalconcentration of staurosporine and the 0% inhibition control consistedof DMSO treated cells. After addition of compounds, assay plates areincubated for 6 days at 37° C., 5% CO₂, relative humidity>90% for 6days. Cell viability is measured by quantization of ATP present in thecell cultures, adding 35 μl of Cell Titer Glo® reagent to the cellplates. Luminescence is read in the SpectraMax M5. The concentrationinhibiting cell viability by 50% is determined using a 4-parametric fitof the normalized dose response curves. IC₅₀ values for this assay arecalculated.

EXAMPLE 9 Derivation of the Lowest Cytotoxic Concentration (LCC)

It is well established that cellular proliferation proceeds through celldivision that results in a doubling of the number of cells afterdivision, relative to the number of cells prior to division. Under afixed set of environmental conditions (e.g., pH, ionic strength,temperature, cell density, medium content of proteins and growthfactors, and the like) cells will proliferate by consecutive doubling(i.e., division) according to the following equation, provided thatsufficient nutrients and other required factors are available.

$\begin{matrix}{N_{t} = {N_{0} \times 2^{\frac{t}{t_{D}}}}} & ( {A{.1}} )\end{matrix}$where N_(t) is the cell number at a time point (t) after initiation ofthe observation period, N₀ is the cell number at the initiation of theobservation period, t is the time after initiation of the observationperiod and t_(D) is the time interval required for cell doubling, alsoreferred to as the doubling time. Equation A.1 can be converted into themore convenient form of an exponential equation in base e, takingadvantage of the equality, 0.693=ln(2).

$\begin{matrix}{N_{t} = {N_{0}{\mathbb{e}}^{\frac{0.693\; t}{t_{D}}}}} & ( {A{.2}} )\end{matrix}$

The rate constant for cell proliferation (k_(p)) is inversely related tothe doubling time as follows.

$\begin{matrix}{k_{p} = \frac{0.693}{t_{D}}} & ( {A{.3}} )\end{matrix}$

Combining equation A.2 and A.3 yields,N _(t) =N ₀ e ^(k) ^(P) ^(t)  (A.4)

Thus, according to equation A.4 cell number is expected to increaseexponentially with time during the early period of cell growth referredto as log-phase growth. Exponential equations like equation A.4 can belinearized by taking the natural logarithm of each side.ln(N _(t))=ln(N ₀)+k _(p) t  (A.5)

Thus a plot of ln(N_(t)) as a function of time is expected to yield anascending straight line with slope equal to k_(p) and y-intercept equalto ln(N₀).

Changes in environmental conditions can result in a change in the rateof cellular proliferation that is quantifiable as changes in theproliferation rate constant k_(p). Among conditions that may result in achange in proliferation rate is the introduction to the system of anantiproliferative compound at the initiation of the observation period(i.e., at t=0). When an antiproliferative compound has an immediateimpact on cell proliferation, one expects that plots of ln(N_(t)) as afunction of time will continue to be linear at all compoundconcentrations, with diminishing values of k_(p) at increasingconcentrations of compound.

Depending on the mechanistic basis of antiproliferative action, somecompounds may not immediately effect a change in proliferation rate.Instead, there may be a period of latency before the impact of thecompound is realized. In such cases a plot of ln(N_(t)) as a function oftime will appear biphasic, and a time point at which the impact of thecompound begins can be identified as the breakpoint between phases.Regardless of whether a compound's impact on proliferation is immediateor begins after a latency period, the rate constant for proliferation ateach compound concentration is best defined by the slope of theln(N_(t)) vs. time curve from the time point at which compound impactbegins to the end of the observation period of the experiment.

A compound applied to growing cells may affect the observedproliferation in one of two general ways: by inhibiting further celldivision (cytostasis) or by cell killing (cytotoxicity). If a compoundis cytostatic, increasing concentration of compound will reduce thevalue of k_(p) until there is no further cell division. At this point,the rate of cell growth, and therefore the value of k_(p), will be zero.If, on the other hand, the compound is cytotoxic, then the value ofk_(p) will be composed of two rate constants: a rate constant forcontinued cell growth in the presence of the compound (k_(g)) and a rateconstant for cell killing by the compound (k_(d)). The overall rateconstant for proliferation at a fixed concentration of compound willthus be the difference between the absolute values of these opposingrate constants.k _(p) =|k _(g) |−|k _(d)|  (A.6)

At compound concentrations for which the rate of cell growth exceedsthat of cell killing, the value of k_(p) will have a positive value(i.e., k_(p)>0). At compound concentrations for which the rate of cellgrowth is less than that for cell killing, the value of k_(p) will havea negative value (i.e., k_(p)<0) and the cell number will decrease withtime, indicative of robust cytotoxicity. When k_(g) exactly matchesk_(d) then the overall proliferation rate constant, k_(p), will have avalue of zero. We can thus define the lowest cytotoxic concentration(LCC) as that concentration of compound that results in a value of k_(p)equal to zero, because any concentration greater than this will resultin clearly observable cytotoxicity. Nota bene: at concentrations belowthe LCC there is likely to be cell killing occurring, but at a rate thatis less than that of residual cell proliferation. The treatment here isnot intended to define the biological details of compound action.Rather, the goal here is to merely define a practical parameter withwhich to objectively quantify the concentration of compound at which therate of cell killing exceeds new cell growth. Indeed, the LCC representsa breakpoint or critical concentration above which frank cytotoxicity isobserved, rather than a cytotoxic concentration per se. In this regard,the LCC can be viewed similar to other physical breakpoint metrics, suchas the critical micelle concentration (CMC) used to define theconcentration of lipid, detergent or other surfactant species abovewhich all molecules incorporate into micellar structures.

Traditionally, the impact of antiproliferative compounds on cell growthhas been most commonly quantified by the IC₅₀ value, which is defined asthat concentration of compound that reduces the rate of cellproliferation to one half that observed in the absence of compound(i.e., for the vehicle or solvent control sample). The IC₅₀, however,does not allow the investigator to differentiate between cytostatic andcytotoxic compounds. The LCC, in contrast, readily allows one to makesuch a differentiation and to further quantify the concentration atwhich the transition to robust cytotoxic behavior occurs.

If one limits the observation time window to between the start of impactand the end of the experiment, then the data will generally fit well toa linear equation when plotted as ln(N_(t)) as a function of time (videsupra). From fits of this type, the value of k_(p) can be determined ateach concentration of compound tested. A replot of the value of k_(p) asa function of compound concentration ([I]) will have the form of adescending isotherm, with a maximum value at [I]=0 of k_(max) (definedby the vehicle or solvent control sample) and a minimum value atinfinite compound concentration of k_(min).

$\begin{matrix}{k_{p} = {\frac{( {k_{\max} - k_{\min}} )}{1 + \frac{\lbrack I\rbrack}{I_{mid}}} + k_{\min}}} & ( {A{.7}} )\end{matrix}$where I_(mid) is the concentration of compound yielding a value of k_(p)that is midway between the values of k_(max) and k_(min) (note that thevalue of I_(mid) is not the same as the IC₅₀, except in the case of acomplete and purely cytostatic compound). Thus, fitting the replot datato equation A.7 provides estimates of k_(max), k_(min) and I_(mid). If acompound is cytostatic (as defined here), the value of k_(min) cannot beless than zero. For cytotoxic compounds, k_(min) will be less than zeroand the absolute value of k_(min) will relate directly to theeffectiveness of the compound in killing cells.

The fitted values derived from equation A.7 can also be used todetermine the value of the LCC. By definition, when [I]=LCC, k_(p)=0.Thus, under these conditions equation A.7 becomes.

$\begin{matrix}{0 = {\frac{( {k_{\max} - k_{\min}} )}{1 + \frac{LCC}{I_{mid}}} + k_{\min}}} & ( {A{.8}} )\end{matrix}$

Algebraic rearrangement of equation A.8 yields an equation for the LCC.

$\begin{matrix}{{LCC} = {I_{mid}\lbrack {( \frac{k_{\max} - k_{\min}}{- k_{\min}} ) - 1} \rbrack}} & ( {A{.9}} )\end{matrix}$

This analysis is simple to implement with nonlinear curve fittingsoftware and may be applied during cellular assays of compound activitythroughout the drug discovery and development process. In this manner,the LCC may provide a valuable metric for the assessment of compound SAR(structure-activity relationship).

EXAMPLE 10 In Vivo Assays

Mice

Female Fox Chase SCID® Mice (CB17/Icr-Prkdc_(scid)/IcrIcoCrl, CharlesRiver Laboratories) or athymic nude mice (Crl:NU(Ncr)-FoxnI_(nu),Charles River Laboratories) are 8 weeks old and had a body-weight (BW)range of 16.0-21.1 g on D1 of the study. The animals are fed ad libitumwater (reverse osmosis 1 ppm Cl) and NIH 31 Modified and Irradiated LabDiet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crudefiber. The mice are housed on irradiated Enrich-o'Cobs™ bedding instatic microisolators on a 12-hour light cycle at 20-22° C. (68-72° F.)and 40-60% humidity. All procedures comply with the recommendations ofthe Guide for Care and Use of Laboratory Animals with respect torestraint, husbandry, surgical procedures, feed and fluid regulation,and veterinary care.

Tumor Cell Culture

Human lymphoma cell lines line are obtained from different sources(ATCC, DSMZ), e.g., WSU-DLCL2 obtained from DSMZ. The cell lines aremaintained at Piedmont as suspension cultures in RPMI-1640 mediumcontaining 100 units/mL penicillin G sodium salt, 100 g/mL streptomycin,and 25 g/mL gentamicin. The medium is supplemented with 10% fetal bovineserum and 2 mM glutamine. The cells are cultured in tissue cultureflasks in a humidified incubator at 37° C., in an atmosphere of 5% CO₂and 95% air.

In Vivo Tumor Implantation

Human lymphoma cell lines, e.g., WSU-DLCL2 cells, are harvested duringmid-log phase growth, and re-suspended in PBS with 50% Matrigel™ (BDBiosciences). Each mouse receives 1×10⁷ cells (0.2 mL cell suspension)subcutaneously in the right flank. Tumors are calipered in twodimensions to monitor growth as the mean volume approached the desired80-120 mm³ range. Tumor size, in mm³, is calculated from:

${{Tumor}\mspace{14mu}{volume}} = \frac{w^{2} \times l}{2}$where w=width and l=length, in mm, of the tumor. Tumor weight can beestimated with the assumption that 1 mg is equivalent to 1 mm₃ of tumorvolume. After 10-30 days mice with 108-126 mm³ tumors are sorted intotreatment groups with mean tumor volumes of 117-119 mm³.Test Articles

Test compounds are stored at room temperature and protected from light.On each treatment day, fresh compound formulations are prepared bysuspending the powders in 0.5% sodium carboxymethylcellulose (NaCMC) and0.1% Tween® 80 in deionized water. Compound 141 (free base) is dissolvedin sterile saline and the pH is adjusted to 4.5 with HCl fresh everyday. The vehicles, 0.5% NaCMC and 0.1% Tween® 80 in deionized water orsterile saline pH 4.5, are used to treat the control groups at the sameschedules. Formulations are stored away from light at 4° C. prior toadministration. Unless otherwise specified, compounds referred to andtested in this experiment are in their specific salt forms mentioned inthis paragraph.

Treatment Plan

Mice are treated at compound doses ranging from 12.5-600 mg/kg and atTID (three time a day every 8 h), BID (2 times a day every 12 h) or QD(once a day) schedules for various amounts of days by oral gavage orinjections via the intraperitoneal route. Each dose is delivered in avolume of 0.2 mL/20 g mouse (10 mL/kg), and adjusted for the lastrecorded weight of individual animals. The maximal treatment length is28 days.

Median Tumor Volume (MTV) and Tumor Growth Inhibition (TGI) Analysis

Treatment efficacy is determined on the last treatment day. MTV(n), themedian tumor volume for the number of animals, n, evaluable on the lastday, is determined for each group. Percent tumor growth inhibition (%TGI) can be defined several ways. First, the difference between theMTV(n) of the designated control group and the MTV(n) of thedrug-treated group is expressed as a percentage of the MTV(n) of thecontrol group:

${\%\mspace{14mu} T\; G\; I} = {( \frac{{M\; T\;{V(n)}_{control}} - {M\; T\;{V(n)}_{treated}}}{M\; T\;{V(n)}_{control}} ) \times 100}$

Another way of calculating % TGI is taking the change of the tumor sizefrom day 1 to day n into account with n being the last treatment day.

${\%\mspace{14mu} T\; G\; I} = {( \frac{{\Delta\; M\; T\; V_{control}} - {\Delta\; M\; T\; V_{treated}}}{\Delta\; M\; T\; V_{control}} ) \times 100}$Δ M T V_(control) = M T V(n)_(control) − M T V(1)_(control)Δ M T V_(treated) = M T V(n)_(treated) − M T V(1)_(treated)Toxicity

Animals are weighed daily on Days 1-5, and then twice weekly until thecompletion of the study. The mice are examined frequently for overtsigns of any adverse, treatment related side effects, which aredocumented. Acceptable toxicity for the maximum tolerated dose (MTD) isdefined as a group mean BW loss of less than 20% during the test, andnot more than 10% mortality due to TR deaths. A death is to beclassified as TR if it is attributable to treatment side effects asevidenced by clinical signs and/or necropsy, or due to unknown causesduring the dosing period. A death is to be classified as NTR if there isevidence that the death is unrelated to treatment side effects. NTRdeaths during the dosing interval would typically be categorized as NTRa(due to an accident or human error) or NTRm (due to necropsy-confirmedtumor dissemination by invasion and/or metastasis). Orally treatedanimals that die from unknown causes during the dosing period may beclassified as NTRu when group performance does not support a TRclassification and necropsy, to rule out a dosing error, is notfeasible.

Sampling

On days 7 or 28 during the studies mice are sampled in a pre-specifiedfashion to assess target inhibition in tumors. Tumors are harvested fromspecified mice under RNAse free conditions and bisected. Frozen tumortissue from each animal is snap frozen in liquid N₂ and pulverized witha mortar and pestle.

Statistical and Graphical Analyses

All statistical and graphical analyses are performed with Prism 3.03(GraphPad) for Windows. To test statistical significance between thecontrol and treated groups over the whole treatment time course arepeated measures ANOVA test followed by Dunnets multiple comparisonpost test or a 2 way ANOVA test are employed. Prism reports results asnon-significant (ns) at P>0.05, significant (symbolized by “*”) at0.01<P<0.05, very significant (“**”) at 0.001<P<0.01 and extremelysignificant (“***”) at P<0.001.

Histone Extraction

For isolation of histones, 60-90 mg tumor tissue is homogenized in 1.5ml nuclear extraction buffer (10 mM Tris-HCl, 10 mM MgCl₂, 25 mM KCl, 1%Triton X-100, 8.6% Sucrose, plus a Roche protease inhibitor tablet1836145) and incubated on ice for 5 minutes. Nuclei are collected bycentrifugation at 600 g for 5 minutes at 4° C. and washed once in PBS.Supernatant is removed and histones extracted for one hour, withvortexing every 15 minutes, with 0.4 N cold sulfuric acid. Extracts areclarified by centrifugation at 10,000 g for 10 minutes at 4° C. andtransferred to a fresh microcentrifuge tube containing 10× volume of icecold acetone. Histones are precipitated at −20° C. for 2hours-overnight, pelleted by centrifugation at 10,000 g for 10 minutes,and resuspended in water.

ELISA

Histones are prepared in equivalent concentrations in coating buffer(PBS+0.05% BSA) yielding 0.5 ng/ul of sample, and 100 ul of sample orstandard is added in duplicate to 2 96-well ELISA plates (ThermoLabsystems, Immulon 4HBX #3885). The plates are sealed and incubatedovernight at 4° C. The following day, plates are washed 3× with 300ul/well PBST (PBS+0.05% Tween 20; 10×PBST, KPL #51-14-02) on a Bio Tekplate washer. Plates are blocked with 300 ul/well of diluent (PBS+2%BSA+0.05% Tween 20), incubated at RT for 2 hours, and washed 3× withPBST. All antibodies are diluted in diluent. 100 ul/well ofanti-H3K27me3 (CST #9733, 50% glycerol stock 1:1,000) or anti-total H3(Abeam ab1791, 50% glycerol 1:10,000) is added to each plate. Plates areincubated for 90 min at RT and washed 3× with PBST. 100 ul/well ofanti-Rb-IgG-HRP (Cell Signaling Technology, 7074) is added 1:2,000 tothe H3K27Me3 plate and 1:6,000 to the H3 plate and incubated for 90 minat RT. Plates are washed 4× with PBST. For detection, 100 ul/well of TMBsubstrate (BioFx Laboratories, #TMBS) is added and plates incubated inthe dark at RT for 5 min. Reaction is stopped with 100 ul/well 1N H₂SO₄.Absorbance at 450 nm is read on SpectaMax M5 Microplate reader.

7 Day PD Study

In order to test whether a compound can modulate the H3K27me3 histonemark in tumors in vivo, WSU-DLCL2 xenograft tumor bearing mice aretreated with the compound at either 200 mg/kg BID or 400 mg/kg QD orvehicle (BID schedule) for 7 days. There are 4 animals per group.Animals are euthanized 3 h after the last dose and tumor is preserved ina frozen state as described above. Following histone extraction thesamples are applied to ELISA assays using antibodies directed againstthe trimethylated state of histone H3K27 (H3K27me3) or total histone H3.Based on these data the ratio of globally methylated to total H3K27 iscalculated. The mean global methylation ratios for all groups asmeasured by ELISA indicates target inhibition range compared to vehicle.

28 Day Efficacy Study in WSU-DLCL2 Xenograft Model

In order to test whether a compound could induce a tumor growthinhibition in vivo WSU-DLCL2 xenograft tumor bearing mice are treatedwith the compound at 12.5, 25 or 50 mg/kg QD for 28 days viaintraperitoneal injection. Tumor volume and body weights are determinedtwice a week. A parallel cohort of mice (n=4 per group) is treated atthe same doses for 7 days, and mice are euthanized on day 7, 3 h afterthe last dose for tumor sampling and assessment of target inhibition.The result of the ELISA measuring global methylation of H3K27me3normalized to total H3 is determined.

Efficacy Study with Increasing Doses in WSU-DLCL2 Xenograft Model

In order to test whether a compound could induce an anti-tumor effect invivo, WSU-DLCL2 xenograft tumor bearing mice are treated with a compoundat, e.g., 37.5, 75 or 150 mg/kg TID for 28 days. There are 12 mice pergroup for the efficacy arm of the experiment. A parallel cohort is dosedfor 7 days at the same doses and schedules for assessment of targetinhibition after 7 days (n=6 per group). The tumor growth over thetreatment course of 28 days for vehicle and compound treated groups ismeasured.

Histones are extracted from tumors collected after 7 days of dosing(parallel PD cohort) and at the end of the study on day 28 for theefficacy cohort (3 h after the last dose for both cohorts). The H3K27me3methyl mark is assessed for modulation with treatment in a dosedependent matter.

Efficacy Study at Different Dose Schedules

To assess whether a compound would lead to tumor growth inhibition atother dosing schedules but TID a WSU-DLCL2 xenograft efficacy study isperformed where TID, BID and QD schedules are compared side by side.There are 12 animals per group, and mice are treated for 28 days. Thetumor growth over the treatment course of 28 days for vehicle andcompound treated groups is measured.

On day 28 mice are euthanized and tumors were collected 3 h after thelast dose for assessment of target inhibition.

EXAMPLE 11 Anti-Cancer Effect on the KARPAS-422 Human Diffused LargeB-Cell Lymphoma Mouse Xenograft Model

A test compound is analyzed for its anti-cancer activity in KARPAS-422mouse xenograft model, which is a human diffused large B-Cell lymphomaxenograft model. 45 female of CAnN.Cg-FoxnlnuCrlCrlj mice (Charles RiverLaboratories Japan) with KARPAS-422 tumors whose mean tumor volume (TV)reached approximately 150 mm³ are selected based on their TVs, and arerandomly divided into five groups. The oral administration of compound(e.g., 80.5, 161, 322, and 644 mg/kg) or vehicle is started on day 1.Compound is given once daily on day 1 and day 29 and twice dailyeveryday from day 2 to day 28. The administration volume (0.1 mL/10 gbody weight) is calculated from the body weight before administration.The TV and body weight were measured twice a week. The design for thisexperiment is shown in Table 5.

TABLE 5 Dosing Scheme No. of Group Animals Treatment (twice a day) Routeand Schedule 1 9 Vehicle (0.5% Methyl Cellulose, PO; BID × 28 days 0.1%Tween-80) 2 9 80.5 mg/kg Compound PO; BID × 28 days 3 9 161 mg/kgCompound PO; BID × 28 days 4 9 322 mg/kg Compound PO; BID × 28 days 5 9644 mg/kg Compound PO; bid × 28 days

TV is calculated from caliper measurements by the formula for the volumeof a prolate ellipsoid (L×W²)/2 where L and W are the respectiveorthogonal length and width measurements (mm).

Data are expressed as the mean±standard deviation (SD). The differencesin TV between the vehicle-treated and compound-treated groups areanalyzed by a repeated measures analysis of variance (ANOVA) followed bythe Dunnett-type multiple comparison test. A value of P<0.05 (two sided)is considered statistically significant. Statistical analyses areperformed using the Prism 5 software package version 5.04 (GraphPadSoftware, Inc., CA, USA).

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound of Formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein X₁ is NR₇ or CR₇; X₂ is N, NR₈, CR₈, O, or S; X₃ is NR₈, CR₈, O,or S; X₄ is C; Y₁ is N; Y₂ is CR₆; Y₃ is CR₁₁; each of R₅, R₉, and R₁₀,independently, is H or C₁-C₆ alkyl optionally substituted with one ormore substituents selected from the group consisting of halo, hydroxyl,COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each R₆independently is H, halo, OR_(a), —NR_(a)R_(b), —C(O)R_(a), —C(O)OR_(a),—C(O)NR_(a)R_(b), —NR_(b)C(O)R_(a), —S(O)₂R_(a), —S(O)₂NR_(a)R_(b), orR_(S2), in which each of R_(a) and R_(b), independently is H or R_(S3)and each of R_(S2) and R_(S3), independently, is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-memberedheterocycloalkyl, or 5 to 6-membered heteroaryl; or R_(a) and R_(b),together with the N atom to which they are attached, form a 4 to7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms tothe N atom; and each of R_(S2), R_(S3), and the 4 to 7-memberedheterocycloalkyl ring containing R_(a) and R_(b), is optionallysubstituted with one or more -Q₂-T₂, wherein Q₂ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₂ is H, halo, cyano, —OR_(c), —NR_(c)R_(d),—(NR_(c)R_(d)R_(d′))⁺A⁻, —C(O)R_(c), —C(O)OR_(c), —C(O)NR_(c)R_(d),—NR_(d)C(O)R_(c), —NR_(d)C(O)OR_(c), —S(O)₂R_(c), —S(O)₂NR_(c)R_(d), orR_(S4), in which each of R_(c), R_(d), and R_(d′), independently is H orR_(S6), A⁻ is a pharmaceutically acceptable anion, each of R_(S4) andR_(S6), independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, or R_(c),and R_(d), together with the N atom to which they are attached, form a 4to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatomsto the N atom, and each of R_(S4), R_(S6), and the 4 to 7-memberedheterocycloalkyl ring containing R_(c) and R_(d), is optionallysubstituted with one or more -Q₃-T₃, wherein Q₃ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₃ is selected from the group consisting of H, halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-memberedheterocycloalkyl, 5 to 6-membered heteroaryl, OR_(e), COOR_(e),—S(O)₂R_(e), —NR_(e)R_(f), and —C(O)NR_(e)R_(f), each of R_(e) and R_(f)independently being H or C₁-C₆ alkyl optionally substituted with OH,O—C₁-C₆ alkyl, or NH—C₁-C₆ alkyl; or -Q₃-T₃ is oxo; or -Q₂-T₂ is oxo; orany two neighboring -Q₂-T₂, together with the atoms to which they areattached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 7-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;provided that -Q₂-T₂ is not H; each R₇ independently is -Q₄-T₄, in whichQ₄ is a bond, C₁-C₄ alkyl linker, or C₂-C₄ alkenyl linker, each linkeroptionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, andT₄ is H, halo, cyano, NR_(g)R_(h), —OR_(g), —C(O)R_(g), —C(O)OR_(g),—C(O)NR_(g)R_(h), —C(O)NR_(g)OR_(h), —NR_(g)C(O)R_(h), —S(O)₂R_(g), orR_(S6), in which each of R_(g) and R_(h), independently is H or R_(S7))each of R_(S6) and R_(S7), independently is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5 to6-membered heteroaryl, and each of R_(S6) and R_(S7) is optionallysubstituted with one or more -Q₅-T₅, wherein Q₅ is a bond, C(O),C(O)NR_(k), NR_(k)C(O), NR_(k), S(O)₂, NR_(k)S(O)₂, or C₁-C₃ alkyllinker, R_(k) being H or C₁-C₆ alkyl, and T₅ is H, halo, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryland T₅ is optionally substituted with one or more substituents selectedfrom the group consisting of halo, C₁-C₆ alkyl, hydroxyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, and 5 to6-membered heteroaryl except when T₅ is H, halo, hydroxyl, or cyano; or—O₅-T₅ is oxo; provided that -Q₄-T₄ is not H; and each R₈ independentlyis H, halo, hydroxyl, COOH, cyano, R_(S8), OR_(S8), or COOR_(S8), inwhich R_(S8) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, amino,mono-C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino, and R_(S8) is optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, and di-C₁-C₆ alkylamino; R₁₁ isH, halo, hydroxyl, COOH, R_(S8), OR_(S8), or COOR_(S8), in which R_(S8)is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, amino, mono-C₁-C₆alkylamino, or di-C₁-C₆ alkylamino, and R_(S8) is optionally substitutedwith one or more substituents selected from the group consisting ofhalo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, and di-C₁-C₆ alkylamino; X is a monocyclic orbicyclic 5 to 10-membered saturated, unsaturated, or aromatic ringcontaining 2-4 heteroatom ring members and optionally substituted withone or more -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃ alkyl linker eachoptionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, andT₇ is H, —OR—, —NR_(n)R_(r), —C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r),—S(O)₂R_(n), —S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) andR_(r), independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl; and n is 1, 2, 3, 4, or 5; provided that at most one of X₂and X₃ is O or S, and X₁, X₂, X₃, X₄, Y₁, Y₂, and Y₃ are assigned suchthat the

 moiety in Formula (I) is a bicyclic heteroaryl system.
 2. The compoundof claim 1, wherein the compound is of Formula (Ia):

wherein R₇ is -Q₄-T₄, wherein Q₄ is a bond or methyl linker, T₄ is C₁-C₆alkyl optionally substituted with one or more -Q₅-T₅, C₃-C₅ cycloalkyloptionally substituted with one or more -Q₅-T₅, or 4- to 14-memberedheterocycloalkyl optionally substituted with one or more -Q₅-T₅.
 3. Thecompound of claim 2, wherein R₇ is tetrahydropyranyl, piperidinesubstituted by 1, 2, or 3 C₁₋₄ alkyl groups, or cyclohexyl substitutedby N(C₁₋₄ alkyl)₂ wherein one or both of the C₁₋₄ alkyl is optionallysubstituted with C₁₋₆ alkoxyl.
 4. The compound of claim 1, wherein R₇ issec-butyl, cyclopentyl, or iso-propyl.
 5. The compound claim 1, whereinR₆ is


6. The compound of claim 1, wherein X is

wherein each of D₁, D₂, and D₃, independently, is CR⁹⁰¹ or N, providedthat at least one of D₁, D₂, and D₃ is N; D₄ is O, S, or NR⁹⁰²; and eachR⁹⁰¹ and R⁹⁰², independently, is -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃alkyl linker each optionally substituted with halo, cyano, hydroxyl orC₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n),—C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), orR_(S9), in which each of R_(n) and R_(r), independently is H or R_(S10),each of R_(S9) and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or6-membered heteroaryl, or R_(n) and R_(r), together with the N atom towhich they are attached, form a 4 to 12-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatom, and each of R_(S9), R_(S10), andthe 4 to 12-membered heterocycloalkyl ring formed by R_(n) and R_(r), isoptionally substituted with one or more -Q₈-T₈, wherein Q₈ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₈ is selected from the group consistingof halo, cyano, C₁-C₆ alkyl, C₃-C₅ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s),COOR_(s), —S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s)and R_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or-Q₇-T₇ is oxo; or any two neighboring —O₇-T₇ together with the atoms towhich they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl.
 7. The compound of claim 1, wherein X is

wherein each of E₁, E₂, and E₄, independently, is CR⁹⁰³ or N, providedthat at least one of E₁, E₂, and E₄ is N; E₃ is O, S, or NR⁹⁰⁴; and eachof R⁹⁰³ and R⁹⁰⁴, independently, is -Q₇-T₇, wherein Q₇ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.
 8. The compound of claim 1, wherein X is

wherein G₁ is O, S, or NR⁹⁰⁷; each of G₂, G₃, and G₄, independently, isN or CR⁹⁰⁸, provided that at least one of G₂, G₃, and G₄ is N; and eachof R⁹⁰⁵, R⁹⁰⁶, R⁹⁰⁷, and R⁹⁰⁸, independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring —O₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈₅ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.
 9. The compound of claim 1, wherein X is

wherein each of J₁, J₂, J₃, and J₄, independently, is N or CR⁹¹¹,provided that at least one of J₁, J₂, J₃, and J₄ is N; and each of R⁹⁰⁹,R⁹¹⁰, and R⁹¹¹, independently, is -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃alkyl linker each optionally substituted with halo, cyano, hydroxyl orC₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n),—C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), orR_(S9), in which each of R_(n) and R_(r), independently is H or R_(S10),each of R_(S9) and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or6-membered heteroaryl, or R_(n) and R_(r), together with the N atom towhich they are attached, form a 4 to 12-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatom, and each of R_(S9), R_(S10), andthe 4 to 12-membered heterocycloalkyl ring formed by R_(n) and R_(r), isoptionally substituted with one or more -Q₈-T₈, wherein Q₈ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₈ is selected from the group consistingof halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s),COOR_(s), —S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s)and R_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or-Q₇-T₇ is oxo; or any two neighboring -Q₇-T₇ together with the atoms towhich they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl.
 10. The compound of claim 1, wherein X is

wherein each of K₁, K₂, K₃, and K₄, independently, is N or CR⁹¹⁴,provided that at least one of K₁, K₂, K₃, and K₄ is N; and each of R⁹¹²,R⁹¹³, and R⁹¹⁴, independently, is -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃alkyl linker each optionally substituted with halo, cyano, hydroxyl orC₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n),—C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), orR_(S9), in which each of R_(n) and R_(r), independently is H or R_(S10),each of R_(S9) and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or6-membered heteroaryl, or R_(n) and R_(r), together with the N atom towhich they are attached, form a 4 to 12-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatom, and each of R_(S9), R_(S10), andthe 4 to 12-membered heterocycloalkyl ring formed by R_(n) and R_(r), isoptionally substituted with one or more -Q₈-T₈, wherein Q₈ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₈ is selected from the group consistingof halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s),COOR_(s), —S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s)and R_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or-Q₇-T₇ is oxo; or any two neighboring -Q₇-T₇ together with the atoms towhich they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl.
 11. The compound of claim 1, wherein X is

wherein each of U₁, U₃, and U₄, independently, is N or CR⁹¹⁷, providedthat at least one of U₁, U₃, and U₄ is N; U₂ is O, S, or NR⁹¹⁸; and eachof R⁹¹⁵, R⁹¹⁶, R⁹¹⁷ and R⁹¹⁸, independently, is -Q₇-T₇, wherein Q₇ is abond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r),—C(O)R_(n), —C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n),—S(O)₂NR_(n)R_(r), or R_(S9), in which each of R_(n) and R_(r),independently is H or R_(S10), each of R_(S9) and R_(S10),independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_(n)and R_(r), together with the N atom to which they are attached, form a 4to 12-membered heterocycloalkyl ring having 0 or 1 additionalheteroatom, and each of R_(S9), R_(S10), and the 4 to 12-memberedheterocycloalkyl ring formed by R_(n) and R_(r), is optionallysubstituted with one or more -Q₈-T₈, wherein Q₈ is a bond or C₁-C₃ alkyllinker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆alkoxy, and T₈ is selected from the group consisting of halo, cyano,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-memberedheterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s), COOR_(s),—S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s) and R_(t)independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or -Q₇-T₇ isoxo; or any two neighboring -Q₇-T₇ together with the atoms to which theyare attached form a 5- or 6-membered ring optionally containing 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-memberedheteroaryl.
 12. The compound of claim 1, wherein X is

wherein each of V₁ and V₂, independently, is N or CR⁹¹⁹, provided thatat least one of V₁ and V₂ is N; V₃ is O, S, or NR⁹²³; each of V₄, V₅,and V₆ is O, S, or NR⁹²¹, or CR⁹²²R⁹²³; and each of R⁹¹⁹, R⁹²⁰, R⁹²¹,R⁹²² and R⁹²³, independently, is -Q₇-T₇, wherein Q₇ is a bond or C₁-C₃alkyl linker each optionally substituted with halo, cyano, hydroxyl orC₁-C₆ alkoxy, and T₇ is H, —OR_(n), —NR_(n)R_(r), —C(O)R_(n),—C(O)OR_(n), —C(O)NR_(n)R_(r), —S(O)₂R_(n), —S(O)₂NR_(n)R_(r), orR_(S9), in which each of R_(n) and R_(r), independently is H or R_(S10),each of R_(S9) and R_(S10), independently, is C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or6-membered heteroaryl, or R_(n) and R_(r), together with the N atom towhich they are attached, form a 4 to 12-membered heterocycloalkyl ringhaving 0 or 1 additional heteroatom, and each of R_(S9), R_(S10), andthe 4 to 12-membered heterocycloalkyl ring formed by R_(n) and R_(r), isoptionally substituted with one or more -Q₈-T₈, wherein Q₈ is a bond orC₁-C₃ alkyl linker each optionally substituted with halo, cyano,hydroxyl or C₁-C₆ alkoxy, and T₈ is selected from the group consistingof halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_(s),COOR_(s), —S(O)₂R_(s), —NR_(s)R_(t), and —C(O)NR_(s)R_(t), each of R_(s)and R_(t) independently being H or C₁-C₆ alkyl, or -Q₈-T₈ is oxo; or-Q₇-T₇ is oxo; or any two neighboring -Q₇-T₇ together with the atoms towhich they are attached form a 5- or 6-membered ring optionallycontaining 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, COOH, C(O)O—C₁-C₆ alkyl, cyano, C₁-C₆alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or6-membered heteroaryl.
 13. The compound of claim 1, wherein X isimidazol-2-yl, imidazol-4-yl, triazol-3-yl,3H-imidazo[4,5-c]pyridin-7-yl, 1H-benzo[d]imidazol-4-yl,1H-indazol-7-yl, isoxazol-3-yl, thiazol-2-yl,1H-pyrazolo[4,3-c]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-c]pyrimidin-8-yl,1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-7-yl,1,4,6,7-tetrahydropyrano[3,4]imidazol-7-yl, or4,5,6,7-tetrahydro-1H-benzo[d]imidazol-4-yl.
 14. The compound of claim1, having the following formula:

wherein Z is selected from

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 16.The compound of Formula (I), wherein R₅ is H, R₇ is sec-butyl,cyclopentyl, isopropyl,

R₉ is H, R₁₀ is H, n is 1 or 2, and R₆ is


17. The compound of Formula (I), wherein R₅ is H, R₉ is H, R₁₀ is H, nis 1 or 2, and R₇ is sec-butyl, cyclopentyl, isopropyl,

wherein R′″ is T₅, —C(O)T₅, or S(O)₂T₅.